Parkinson’s disease

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Parkinson’s disease

Parkinson’s disease is a progressive degenerative disorder of the basal ganglia that affects the initiation and execution of voluntary movements (and is usually associated with a tremor). It is the second most common neurodegenerative disorder after Alzheimer’s disease. The lifetime risk is 0.1%, but the incidence increases with age and the prevalence is 1–2% in people over 65. The mean age at onset is 60 and it is more common in males. Although there is no cure, symptoms can usually be well controlled for several years with dopamine replacement therapy (discussed below).

Clinical features

Most cases of Parkinson’s disease are idiopathic (meaning that the cause is not known). The main symptoms and signs of idiopathic Parkinson’s disease (IPD) are illustrated in Figure 13.1. The central feature is akinesia or poverty of movement (Greek: a-, without; kinesis, movement) together with marked muscular rigidity. It is therefore classified as an akinetic-rigid syndrome. Another prominent component is bradykinesia, meaning that movements are slow and deliberate (Greek: bradys, slow). In most cases there is also a coarse tremor. Parkinson’s disease is sometimes referred to as an extrapyramidal movement disorder since the pyramidal (primary motor) pathway is unaffected.

Fig. 13.1 Features of idiopathic Parkinson’s disease.
The combination of a flexed posture, slow shuffling gait, mask-like facial expression and unilateral tremor is highly characteristic.

Other features

Non-motor symptoms in Parkinson’s disease reflect: (i) the role of the basal ganglia in cognition, emotion and behaviour (see Ch. 3); and (ii) the presence of widespread pathological changes in the brain stem, limbic lobe and neocortex. Anxiety, depression or apathy occurs in 40% of patients. There may be sleep disorders including: nocturnal hallucinations, excessive daytime somnolence, vivid dreams, nightmares or sleepwalking. Subtle cognitive changes are common, such as bradyphrenia (generalized slowing of thought) or executive dysfunction (difficulty with organization, planning and decision-making). One in five patients will eventually be diagnosed with dementia (Clinical Box 13.1).

Clinical Box 13.1: Dementia in Parkinson’s disease

Dementia occurs in at least 20% of patients with Parkinson’s disease, usually after a number of years. If cognitive decline appears 12 months or more after the onset of parkinsonian features, then the term Parkinson’s disease with dementia (PDD) is used. If cognitive decline occurs within a year of presentation (or at the same time as the motor features) then a diagnosis of dementia with Lewy bodies (DLB) may be made. Specific features of DLB, in addition to parkinsonism, include fluctuations in cognitive performance and visual hallucinations. It is important to note that the distinction between PDD and DLB is purely clinical, since the pathological changes are identical (see Ch. 12 for further discussion of dementia, including features that distinguish DLB from Alzheimer’s disease).

Diagnosis and course

The diagnosis of Parkinson’s disease is primarily clinical. Routine MRI scans are often normal, but dopamine deficiency in the basal ganglia can be demonstrated using specialized tests (Fig. 13.3). Without treatment there is progressive decline over a 5–10-year period, with gradual deterioration of motor function, worsening postural instability, gait freezing and frequent falls. However, symptoms can usually be controlled for a number of years with dopamine replacement therapy and this is associated with a near-normal life expectancy.

Fig. 13.3 Functional imaging of dopamine transport in Parkinson’s disease.
**(A)** Axial section through the basal ganglia showing the normal pattern of uptake in a healthy control. The characteristic ‘comma’ shape of the striatum (caudate nucleus and putamen) is seen; **(B)** In a patient with Parkinson’s disease, there is markedly reduced signal in the putamen but not in the head of the caudate nucleus, creating a ‘full stop’ appearance. [Images obtained using single photon emission computed tomography (SPECT) with the radioactively labelled (¹²³I) beta-CIT.] From Seibyl, JP: Single-photon emission computed tomography and positron emission tomography evaluations of patients with central motor disorders. J Semin Nuclear Med (2008) with permission.

Key Points

Idiopathic Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1–2% of people over the age of 65.

The central feature is akinesia (poverty of movement). This is accompanied by bradykinesia (slow initiation and execution of movements), ‘lead-pipe’ rigidity and impaired postural reflexes.

Tremor occurs in 75% of patients. It is not an invariable feature, but a classic ‘pill-rolling’ tremor is virtually diagnostic of idiopathic Parkinson’s disease.

Mood disorder occurs in about 40% of patients and subtle cognitive changes are common. One in five patients will eventually develop dementia, usually after a number of years.

Parkinsonism

Some patients presenting with an akinetic-rigid syndrome do not have idiopathic Parkinson’s disease. This is referred to as parkinsonism and there are many underlying causes. Response to dopamine replacement tends to be poor, symptoms are typically more symmetric in distribution and there may be other atypical features such as gaze palsy, axial rigidity, early falls or pyramidal tract signs. The most common forms are drug-induced, vascular and neurodegenerative.

Drug-induced parkinsonism

Administration of antipsychotic (neuroleptic) agents may cause ‘extrapyramidal side effects’ that mimic Parkinson’s disease and this is the most common cause of parkinsonism. It occurs because neuroleptic drugs antagonize central dopamine receptors, including those within the basal ganglia.

Vascular pseudoparkinsonism

Patients with cerebrovascular disease may develop an akinetic-rigid syndrome. This is due to microinfarcts (small ischaemic strokes, see Ch. 10) in the basal ganglia or hemispheric white matter. In contrast to idiopathic Parkinson’s disease, symptoms tend to be more severe in the lower limbs, response to dopamine replacement is poor and tremor is usually absent.

Neurodegenerative causes

A number of other neurodegenerative disorders may be confused with Parkinson’s disease. The most important are progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), each with a prevalence of approximately 1 in 20,000. An even rarer form is corticobasal degeneration (CBD), discussed in Clinical Box 13.2.

Clinical Box 13.2: Corticobasal degeneration

This is a rare neurodegenerative disease of the cerebral cortex and basal ganglia that affects less than 1 in 100,000 people. Clinical features include parkinsonism (that responds poorly to dopamine replacement) together with limb apraxia, pyramidal tract signs and frontotemporal dementia. It often presents with a single clumsy or apraxic limb. Some patients experience autonomous hand or arm movements, referred to as an alien limb. CBD may also present as an isolated dementia syndrome without parkinsonian features.

Progressive supranuclear palsy

This is the most common neurodegenerative mimic of Parkinson’s disease, accounting for about 5% of people with a parkinsonian syndrome. In more than 50% of cases there is axial rigidity, a hyperextended posture and a characteristic supranuclear gaze palsy with failure in the cortical (‘supranuclear’) control of vertical eye movements. There may also be apathy, cognitive decline and outbursts of inappropriate laughter or tearfulness, termed emotional incontinence. This classical form of PSP is also referred to as Richardson’s syndrome. In up to a third of cases the clinical features closely resemble idiopathic Parkinson’s disease. In this subtype, referred to as PSP-P, the pathological changes are less severe and the clinical course is more favourable. Features of PSP and Parkinson’s disease are compared in Figure 13.4.

Multiple system atrophy

Multiple system atrophy is characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. There are two patterns. MSA-P is dominated by rigidity, bradykinesia and postural instability and closely resembles idiopathic Parkinson’s disease; whereas MSA-C combines features of cerebellar ataxia with corticospinal tract signs including increased muscle tone and reflexes (see Ch. 4).

Multiple system atrophy encompasses three entities that were previously regarded as separate diseases: striatonigral degeneration (corresponding to MSA-P), olivopontocerebellar atrophy or OPCA (corresponding to MSA-C) and the Shy–Drager syndrome (representing a form of primary autonomic failure). Autonomic features such as postural hypotension and erectile dysfunction may occur in both MSA-C and MSA-P and also in idiopathic Parkinson’s disease.

Key Points

Akinetic-rigid syndromes other than idiopathic Parkinson’s disease are referred to as parkinsonism. The main causes are drug-induced, vascular and neurodegenerative.

The most common form of parkinsonism is seen in patients taking antipsychotic agents, which work by antagonizing central dopamine receptors (‘extrapyramidal side effects’).

Vascular pseudoparkinsonism is due to small infarcts in the basal ganglia or their white matter connections.

The most common neurodegenerative mimic of Parkinson’s disease is progressive supranuclear palsy (PSP), characterized by axial rigidity, hyperextended posture and vertical gaze palsy.

Others include multiple system atrophy (with parkinsonian and cerebellar subtypes: MSA-P and MSA-C) and the much less common corticobasal degeneration (CBD).

Pathology of Parkinson’s disease

The key pathological change in Parkinson’s disease is loss of dopaminergic neurons in the substantia nigra of the midbrain (Fig. 13.5). This is associated with degeneration of the nigrostriatal tract, leading to a profound reduction of dopamine in the basal ganglia (typically below 20% of normal at presentation). Surviving nigral neurons contain cytoplasmic inclusions called Lewy bodies, which can be identified by antibody labelling for the major component, alpha-synuclein protein. This reveals widespread pathological changes throughout the brain stem, limbic lobe and neocortex.

Fig. 13.5 Degeneration of the substantia nigra in Parkinson’s disease.
**(A)** Normal midbrain (in cross section) with a deeply pigmented substantia nigra; **(B)** Pallor of the substantia nigra in a case of Parkinson’s disease. From Kumar et al: Robbins and Cotran’s Pathologic Basis of Disease 7e (Saunders 2004) with permission.

Neuronal loss

The substantia nigra is a large midbrain nucleus that can be divided into compact and reticular parts. The pars compacta contains the cell bodies of dopaminergic neurons contributing to the nigrostriatal tract, whereas the pars reticulata consists of GABAergic neurons and is analogous to the globus pallidus. The substantia nigra is almost black in the adult brain (Latin: nigra, black) due to the accumulation of neuromelanin as a by-product of dopamine synthesis (see Ch. 7). Loss of dopaminergic neurons in Parkinson’s disease causes pallor of the substantia nigra which can be seen at post-mortem examination. The lateral part of the substantia nigra (which projects to the putamen or ‘motor striatum’) is more severely affected than the medial portion (which projects to the caudate nucleus).

Neuronal loss is also seen in other parts of the nervous system in patients with Parkinson’s disease. These include the noradrenergic locus coeruleus of the pons (see Ch. 1). Post-mortem examination of the brain in Parkinson’s disease may therefore show pallor of the loci coerulei as well as the substantia nigra. Despite normal age-related degeneration of the substantia nigra, most people have sufficient reserve capacity so that striatal dopamine levels never fall below 20% of normal.

Lewy bodies

The pathological hallmark of Parkinson’s disease is the Lewy body (Fig. 13.6). This is a type of pathological inclusion (abnormal protein aggregate) found in the cytoplasm of surviving neurons. Lewy bodies are spherical structures, measuring 5–30 µm in diameter. They are pink on standard histological preparations (because they take up the red tissue dye eosin) and are surrounded by a pale halo.

Fig. 13.6 Lewy bodies.
**(A)** On routine haematoxylin and eosin (H&E)-stained sections Lewy bodies appear as bright pink structures in the neuronal cytoplasm, surrounded by a pale halo; **(B)** They can also be demonstrated by immunohistochemistry for alpha-synuclein protein, which is the main constituent. Courtesy of Professor Steve Gentleman.

Progression of Lewy body pathology

Lewy body pathology begins in the medulla and olfactory bulbs, spreading progressively through six Braak stages to involve the pons, midbrain, limbic lobe, amygdala and neocortex (Fig. 13.7). Cortical Lewy bodies are similar to those encountered in the brain stem, but do not have a halo and are present even in cases without dementia. Pathological inclusions are also found in the autonomic nervous system, including the enteric nervous system in the gastrointestinal tract.

Spread of Lewy body pathology may reflect selective vulnerability of certain brain regions (so that they are affected earlier) or could be due to stepwise spread along anatomical pathways. Since the olfactory bulb is affected first, the possibility of a pathogenic virus infection gaining access to the brain via the nasal mucosa has been postulated.

Alpha-synuclein

The main constituent of Lewy bodies is alpha-synuclein. This is a synaptic protein that is present in presynaptic terminals in association with synaptic vesicles. It seems to be involved in neurotransmitter release and synaptic plasticity (which is critical for learning and memory; see Ch. 7). It may also take part in the regulation of dopamine storage and synaptic vesicle recycling.

The synuclein gene (SNCA, on chromosome 4) has six exons and encodes a natively unfolded 140-amino-acid protein. This has three domains, including a central hydrophobic region that is involved in protein aggregation. The most common familial forms of Parkinson’s disease are caused by duplications or triplications of the synuclein gene. In other cases SNCA point mutations encourage alpha-synuclein aggregation and Lewy body formation.

Accumulation of alpha-synuclein (within neurons and glia) occurs in several other parkinsonian syndromes including Parkinson’s disease with dementia, dementia with Lewy bodies (DLB) and MSA (Fig. 13.8) which are all classified as synucleinopathies. In other forms of parkinsonism such as PSP and CBD there is accumulation of the microtubule-associated protein tau and these disorders are therefore classified as tauopathies. The molecular classification of neurodegenerative diseases is discussed in Ch. 8.

Fig. 13.8 Synucleinopathies such as Parkinson’s disease and multiple system atrophy (MSA) are characterized by pathological neuronal and glial inclusions composed of alpha-synuclein protein.
This microscopic image shows glial cytoplasmic inclusions (GCIs) within oligodendrocytes in a case of MSA, highlighted by immunohistochemistry (antibody labelling). Courtesy of Professor Steve Gentleman.

Key Points

The key pathological change in idiopathic Parkinson’s disease is loss of dopaminergic neurons in the substantia nigra (pars compacta) of the midbrain, resulting in degeneration of the nigrostriatal tract.

This leads to profound reduction in striatal dopamine (<20% of normal at presentation). The projection to the putamen (‘motor striatum’) is most severely affected, with less pronounced dopamine deficiency in the caudate nucleus.

The pathological hallmark of Parkinson’s disease is the Lewy body, a cytoplasmic neuronal inclusion composed predominantly of the synaptic protein alpha-synuclein.

Lewy body pathology begins in the olfactory bulb and medulla, progressing through six Braak stages to involve the pons, midbrain, amygdala, limbic lobe and neocortex.

Familial Parkinson’s disease

Five to ten percent of Parkinson’s disease is familial. Around a dozen genes have been identified and the six best understood are shown in Figure 13.9. Some genes have one name connected with the protein encoded and another that is based on the order of discovery (PARK1, PARK2, etc.). The names can be confusing (for instance, it turns out that PARK1 and PARK4 are the same gene).

Autosomal dominant PD

The first Parkinson’s disease gene to be identified was SNCA (also known as PARK1/PARK4), which encodes alpha-synuclein. This led to the discovery that alpha-synuclein is the main constituent of Lewy bodies. The gene was identified by genetic linkage analysis in a large Italian family known as the Contursi kindred. This family carries an alanine to threonine point mutation (A53T) in the alpha-synuclein gene on chromosome 4. Different point mutations (A30P, E46K) have been found in other families, all of which produce a severe, autosomal dominant Parkinson’s disease with variable penetrance. The clinical and pathological features are similar to sporadic Parkinson’s disease.

The most common form of autosomal dominant Parkinson’s disease is caused by mutation of the leucine-rich repeat kinase 2 gene (LRRK2/PARK8). This is a large gene composed of 51 exons which encodes a 2,527-amino-acid protein called Dardarin (Basque: dadara, tremor). The protein is part of an intracellular second messenger cascade which activates intracellular kinases. A number of pathogenic mutations have been identified. These produce a late-onset, dopamine-responsive parkinsonian syndrome that resembles idiopathic Parkinson’s disease.

Autosomal recessive PD

Mutations in the genes that encode the proteins Parkin, PINK1 and DJ1 all cause a similar dopamine-responsive parkinsonism with dystonia (abnormal muscle tone and posture).

With Parkin gene (PARK2) mutations, disease onset is usually below the age of 40 years and these mutations account for 50% of autosomal recessive juvenile parkinsonism (ARJP). Parkin is a ubiquitin-ligase which is involved in ubiquitination and targeting of proteins for degradation by the proteasome (discussed below; see also Ch. 8). Most Parkin gene mutations reduce the ability to form protein aggregates and Lewy bodies are therefore absent.

PINK1 (PTEN-induced kinase 1) is a serine/threonine protein kinase that translocates to mitochondria and is thought to protect cells from stress-induced mitochondrial dysfunction. Mutations in the PINK1 gene (PINK1/PARK6) explain around 5% of autosomal recessive Parkinson’s disease.

DJ1 is a molecular chaperone protein that prevents aggregation of synuclein and also seems to protect against oxidative stress. Mutations in the DJ1 gene (PARK7) account for a small proportion of autosomal recessive parkinsonism.

Mutations in the ATPase Type 13A2 gene (ATP13A2/PARK9) are associated with juvenile-onset autosomal recessive Parkinson’s disease which is accompanied by hallucinations, cognitive changes, gaze palsy and pyramidal tract signs. The gene encodes a lysosomal ATPase that is present at high concentration in the substantia nigra and may be involved in degradation of alpha-synuclein.

Key Points

Five to ten percent of Parkinson’s disease is familial and may be autosomal dominant or recessive.

The first gene to be identified was SNCA (the alpha-synuclein gene) which causes an autosomal dominant parkinsonism with features similar to idiopathic Parkinson’s disease.

The other familial forms have variable clinical and pathological features, some with dystonia (abnormal muscle tone and posture).

Parkin gene (PARK2) mutations account for 50% of autosomal recessive juvenile parkinsonism (ARJP). These cases do not have Lewy bodies.

Treatment of Parkinson’s disease

The core features of Parkinson’s disease can be treated by replacing striatal dopamine, enhancing transmission at dopaminergic synapses or by stimulating dopamine receptors (see Fig. 13.10; and discussion in following sections).

Dopamine replacement

The mainstay of treatment for idiopathic Parkinson’s disease is levodopa (or L-dopa), the amino acid precursor of dopamine. Levodopa (L-3,4-dihydroxyphenylalanine) is absorbed orally and, unlike dopamine, readily crosses the blood–brain barrier. It does so via the transport mechanism for large neutral amino acids. Levodopa is first taken up by dopaminergic neurons and astrocytes, then converted to dopamine by dopa decarboxylase. Dopamine can be stored by surviving nigral neurons and released at striatal synapses. It is also liberated directly into the interstitial fluid by astrocytes.

Levodopa is a prodrug because it has to be taken up by neurons and glia where it is converted to the active drug, dopamine. Peripheral activation would release dopamine into the bloodstream, causing hypotension and nausea (Clinical Box 13.3). Uptake by sympathetic neurons and conversion to noradrenaline would also interfere with autonomic control of the cardiovascular system. These side effects are avoided by co-administration of a dopa-decarboxylase inhibitor that is unable to cross the blood–brain barrier, increasing availability to the brain and significantly reducing the oral dose. Two commonly used peripheral decarboxylase inhibitors are carbidopa and benserazide (contained in combined preparations: co-careldopa and co-beneldopa).

Clinical Box 13.3: Nausea in Parkinson’s disease

Nausea is a common side effect of Parkinson’s disease drugs, due to stimulation of dopamine receptors in the emetic (vomiting) centre of the medulla. It can be treated with domperidone, a dopamine receptor antagonist that does not cross the blood–brain barrier and cannot therefore interfere with central dopamine receptors. It acts directly at the chemoreceptor trigger zone of the emetic centre, which lies outside of the blood–brain barrier. Most anti-emetic agents are unsuitable as they block central dopamine receptors and exacerbate parkinsonism.

Problems with levodopa therapy

Levodopa provides excellent symptomatic control in early Parkinson’s disease, but in the later stages its efficacy gradually declines and a number of debilitating side effects emerge.

Reduction in efficacy

With time, single doses of levodopa wear off sooner, causing end-of-dose fluctuations in motor performance. There may be unpredictable shifts from a mobile (‘on’) state to an immobile (‘off’) state which can be very disabling.

Loss of effectiveness may be due to the natural progression of the disease. For instance, as nigral neurons continue to degenerate there is reduced capacity for neurotransmitter synthesis and storage, so that striatal dopamine levels are increasingly dependent on the plasma concentration. Competition for uptake into the brain via the transporter for large neutral amino acids may therefore become more important and striatal dopamine levels may fall after protein-rich meals.

Delivery of dopamine can be evened out by modified-release preparations or by continuous gastrointestinal delivery, via a tube inserted into the jejunum.

Side-effects of levodopa

Patients on long-term levodopa therapy develop disabling dyskinesias (involuntary movements). This occurs at a rate of approximately 10% of patients per year. It does not happen in the natural history of Parkinson’s disease and represents a specific side effect of dopamine replacement therapy.

Excessive dopaminergic stimulation may also cause psychotic features which may be difficult to manage as most antipsychotic agents block central dopamine receptors and therefore exacerbate parkinsonism. Some patients respond to ‘atypical’ neuroleptics (e.g. clozapine) which also antagonize serotonin receptors. Other side effects include confusion and behavioural changes (Clinical Box 13.4).

Clinical Box 13.4: Dopamine dysregulation syndrome

A small percentage of patients with Parkinson’s disease become ‘addicted’ to their medication and use much higher doses than they need. This is associated with impulse control problems (e.g. hypersexuality, pathological gambling, over-eating, over-spending). Another feature is punding, the compulsive repetition of purposeless actions (e.g. lining up objects in rows). Dopamine dysregulation syndrome is thought to be caused by over-stimulation of dopamine receptors in the ventral striatum, part of the basal ganglia that is known to be involved in reward-based learning and addiction (see Ch. 3).

Other agents

Other drugs used to treat the symptoms of Parkinson’s disease include dopamine receptor agonists, enzyme inhibitors (see Fig. 13.10) and anticholinergic agents.

Anticholinergics

Anticholinergics such as benztropine and benzhexol provide modest symptomatic benefit (by an uncertain mechanism) and are more effective in treating tremor than akinesia or rigidity. These agents may also offer some improvement in drooling and urinary frequency. Side effects include blurred vision, constipation, memory loss and confusion (which are more problematic in the elderly).

Amantadine

This was originally used as an antiviral agent to treat influenza, but provides mild symptomatic benefit in early Parkinson’s disease. It can be used as a dopamine-sparing agent, delaying the onset of levodopa-associated side effects and loss of efficacy. Amantadine increases dopamine release and reduces its reuptake. It is also a weak antagonist at the NMDA glutamate receptor (see Ch. 7). The beneficial effect of amantadine is modest overall and tends to wear off after a few weeks. Side effects include ankle oedema, skin rash, confusion and hallucinations.

Enzyme inhibitors

Inhibitors of catechol-O-methyltransferase (COMT) such as entacapone and tolcapone block degradation of levodopa. This boosts the effective plasma half-life and increases the amount available to enter the brain. These agents are therefore similar to peripheral decarboxylase inhibitors. COMT inhibitors tend to cause gastrointestinal side effects including diarrhoea and liver toxicity.

Inhibitors of monoamine oxidase prevent degradation of dopamine and therefore prolong its action. Specific inhibitors of the central nervous system isoform (MAO-B) such as selegiline have been used in early Parkinson’s disease to delay initiation of levodopa therapy. It has been suggested that selegiline might slow disease progression by blocking conversion of a putative environmental agent to its neurotoxic form, but this has not been proven.

Dopamine receptor agonists

Numerous dopamine receptor agonists are used in the treatment of Parkinson’s disease, such as pramipexole and ropinirole (others include lisuride, bromocriptine and cabergoline). They are not as effective as levodopa, but may be less likely to cause dyskinesias and can be used to delay administration of levodopa or reduce the required dose.

The effectiveness of a dopamine agonist depends in part on its receptor specificity. An ideal drug would stimulate both main types of dopamine receptor (D1 and D2). Apomorphine is such an agent, but can only be administered by subcutaneous infusion via a syringe driver, which makes it more expensive and less practical.

Key Points

The mainstay of Parkinson’s disease treatment is levodopa, a prodrug which is able to cross the blood–brain barrier where it is taken up by neurons/glia and converted to dopamine.

It is administered as a combined preparation together with a peripheral decarboxylase inhibitor (e.g. carbidopa or benserazide) to minimise unwanted systemic effects.

Nausea is a common side effect of drugs used in the management of Parkinson’s disease and can be treated with domperidone, a dopamine receptor antagonist that does not cross the blood–brain barrier.

The efficacy of levodopa treatment gradually falls over time, so that: (i) single doses wear off sooner; (ii) there are unpredictable ‘end-of-dose fluctuations’ in motor performance; and (iii) the patient may experience abrupt shifts from a mobile ‘on’ state to an immobile ‘off’ state.

In addition, patients on long-term levodopa therapy tend to develop disabling dyskinesias (involuntary movements). This occurs at a rate of approximately 10% of patients per year.

Dopamine receptor agonists (e.g. pramipexole, ropinirole) are also used in the treatment of Parkinson’s disease. They are not as effective, but less likely to cause drug-induced dyskinesias.

Other agents include: anticholinergics (e.g. benztropine, benzhexol) which may be particularly helpful in tremor; amantadine (an antiviral agent that increases dopamine availability); and inhibitors of enzymes that degrade dopamine or levodopa (e.g. COMT, MAO).

Surgery in Parkinson’s disease

Neurosurgery may be an option in longstanding Parkinson’s disease that is no longer responsive to levodopa, particularly in patients with severe dyskinesias and no evidence of dementia. Destructive lesions in the thalamus or pallidum (thalamotomy and pallidotomy) can be effective and a small number of patients have received experimental transplants from the substantia nigra of fetuses (Clinical Box 13.5). However, the most successful surgical approach involves the placement of deep brain electrodes which are used to stimulate various parts of the basal ganglia.

Clinical Box 13.5: Fetal nigral transplants

Some patients with Parkinson’s disease have received neuronal transplants from the substantia nigra of fetuses (obtained following elective termination of pregnancy). Fetal nigral cells are grafted directly into the striatum where they have been shown to form synapses, synthesize dopamine and accumulate neuromelanin. Increased striatal dopamine has also been confirmed by PET scanning. However, the effect on parkinsonian symptoms in most patients has been disappointing and post-mortem studies in long-term survivors show that grafted cells also degenerate and eventually develop Lewy bodies (providing an important clue to the pathogenesis of Parkinson’s disease).

Deep brain stimulation (DBS)

Using a stereotactic frame and MRI guidance (Fig. 13.11) it is possible to implant electrodes at precise subcortical targets, deep within the brain. Specific nuclei can then be stimulated via a subcutaneous pacemaker in the chest. The main surgical risks are intracerebral haemorrhage and infection, but serious complications occur in less than 2% of cases in specialist centres.

Fig. 13.11 Surgery in Parkinson’s disease.
Intraoperative photograph of a patient wearing a stereotactic frame undergoing functional neurosurgery for drug-resistant Parkinson’s disease. From Larson, PS: Neurosurg Clin North Am 2010; 21(4): 691–698, with permission.

The most effective approach is bilateral stimulation of the subthalamic nucleus (Fig. 13.12) which provides excellent relief of akinesia and bradykinesia. It also allows the oral levodopa dose to be reduced and improves dopa-induced dyskinesias. Other DBS targets include the thalamus (particularly in people with severe, drug-resistant tremor) and, much less commonly, the pedunculopontine nucleus at the junction of the midbrain and pons (a small brain stem structure that is involved in gait initiation and is known to degenerate in Parkinson’s disease).

Fig. 13.12 The subthalamic nucleus (STN) is an important target for deep brain stimulation in Parkinson’s disease.
This small, lens-shaped nucleus belongs to the basal ganglia. It lies just below the thalamus, close to the substantia nigra and posterior limb of the internal capsule.

The effect of deep brain stimulation on the target structure depends on stimulation frequency. Low-frequency stimulation (<80 Hz) appears to be excitatory, whereas stimulation at higher frequencies (>130 Hz) inhibits the target nucleus by an uncertain mechanism. This may be due to depolarization blockade (similar to the way that muscle-relaxant drugs work) or neurotransmitter depletion.

Key Points

Neurosurgery may be an option in longstanding Parkinson’s disease that is no longer responding to levodopa, particularly in patients with severe dyskinesias and no evidence of dementia.

Destructive lesions in the thalamus and globus pallidus (thalamotomy and pallidotomy) have largely been replaced by deep brain stimulation (DBS).

The most successful approach is bilateral stimulation of the subthalamic nucleus (STN) which provides excellent relief of both akinesia and bradykinesia. Surgery also permits a reduction in the oral levodopa dose, decreasing the risk of dopa-induced dyskinesias.

Some patients with Parkinson’s disease have received striatal transplants from the substantia nigra of fetuses, but clinical trials have been disappointing and post-mortem studies in long-term survivors show that grafted cells also degenerate and develop Lewy bodies.

Pathophysiology

The anatomy of the corpus striatum, its functional divisions and the concept of basal ganglia loops (including their non-motor roles in cognition, emotion and behaviour) have been introduced in Chapter 3. This section will explore the contribution of the basal ganglia to voluntary movement and how this is disturbed in Parkinson’s disease.

The voluntary motor loop

Initiation of voluntary actions involves a basal ganglia loop that originates and terminates in the supplementary motor area (SMA) (Fig. 13.13; see also Ch. 3). Activity in the SMA and voluntary motor loop is facilitated by dopamine, which lowers the threshold for movement initiation. This helps to determine whether an intention to act is translated into an actual movement. Reduced activity in the SMA (due to striatal dopamine deficiency) is responsible for the akinesia (poverty of movement) in Parkinson’s disease.

Fig. 13.13 Voluntary motor loop of the basal ganglia.
The central, ‘closed loop’ component originates and terminates in the supplementary motor area (SMA) in the medial frontal lobe (see Ch. 3, Fig. 3.4b). Other sensory and motor areas form ‘open-loop’ components.

The SMA is involved in self-initiated actions (e.g. throwing a ball, rising from a chair) rather than movements that occur in response to an external stimulus or trigger (e.g. catching a ball, stepping over a piece of chalk). This has been exploited with the creation of virtual reality glasses that provide artificial visual cues for parkinsonian patients (projections of horizontal lines to ‘step over’). This leads to improvement in gait initiation, stride length and pace, with fewer falls. In some cases, powerful emotions can overcome akinesia (Clinical Box 13.6).

Clinical Box 13.6: Paradoxical kinesis

A strong sense of urgency or fear can sometimes overcome akinesia in patients with Parkinson’s disease. The classic example is the profoundly akinetic patient who is suddenly able to run freely from a burning building, only to ‘freeze’ again once he reaches a place of safety. This is referred to as paradoxical kinesis and may be mediated by projections from the amygdala to the ventral striatum which is the ‘limbic’ (emotion-related) portion of the basal ganglia (see Ch. 3).

Key Points

Initiation of voluntary movement is associated with increased activity in the supplementary motor area (SMA) and voluntary motor loop, which is facilitated by dopamine.

The SMA is particularly involved in self-initiated (rather than externally triggered) actions and this type of movement is most affected in Parkinson’s disease.

In addition to the well-known (and best-understood) roles in motor control, the basal ganglia also contribute to numerous aspects of cognition, behaviour and mood.

Afferent and efferent connections

To understand how activity in the basal ganglia loops contributes to normal and disordered voluntary motor control, it is first necessary to review the general arrangement of the basal ganglia connections.

Projections into the basal ganglia

All basal ganglia loops arise and terminate in the frontal lobe. The frontal cortex projects to the striatum (caudate-putamen) which is therefore the afferent (or ‘input’) part of the basal ganglia. Cortical afferents terminate on medium spiny neurons, which make up 95% of basal ganglia cells. They are so-named because they have medium-sized cell bodies and numerous dendritic spines (Fig. 13.14). The head of each spine receives a single afferent projection from the frontal cortex, whereas the shaft receives a dopaminergic projection from the nigrostriatal pathway (which has a modulating effect). It is important to note that the vast majority of intrinsic basal ganglia cells are GABAergic and that the outflow of the basal ganglia is entirely inhibitory.

Fig. 13.14 Medium spiny neurons in the striatum.
**(A)** Approximately 95% of basal ganglia neurons are classified as ‘medium spiny’ cells. Several medium spiny striatal neurons are illustrated in the figure: some projecting to the external pallidum, others projecting to the internal pallidum. These two types of neuron belong to the ‘indirect’ and ‘direct’ pathways, respectively [see text for further discussion]; **(B)** Medium spiny neurons in the striatum (caudate nucleus/putamen) receive excitatory projections from the frontal lobe. These excitatory cortico-striatal projections terminate on the heads of dendritic spines. In contrast, dopaminergic projections (from the substantia nigra) synapse on the shafts of dendritic spines, facilitating direct pathway neurons but inhibiting those belonging to the indirect pathway.

Outflow of the basal ganglia

The outflow of the basal ganglia arises from the internal pallidum (internal segment of the globus pallidus). The pars reticulata of the substantia nigra (SNpr) is functionally homologous and performs an equivalent role in an oculomotor loop that controls voluntary gaze. The internal pallidum/SNpr is therefore the efferent (or ‘output’) part of the basal ganglia and is entirely inhibitory.

By default, the internal pallidum inhibits thalamocortical neurons that take part in basal ganglia loops. The ‘default action’ of the basal ganglia is thus to prevent unwanted movements, thoughts and behaviours (Fig. 13.15). Although tonically active, the internal pallidum is also constantly stimulated by the subthalamic nucleus, which is excitatory and glutamatergic. This reinforces the ‘default state’ of pallidal inhibition and explains why destruction of the subthalamic nucleus causes involuntary movements (Clinical Box 13.7).

Clinical Box 13.7: Hemiballismus

Hemiballismus is a rare condition characterized by violent flinging movements on one side of the body (Greek: hemi, half; ballismos, jumping). It is usually caused by a small stroke (Ch. 10) affecting the subthalamic nucleus, which normally helps to block unwanted movements by exciting the internal pallidum (which is the inhibitory outflow nucleus or ‘brake’ of the basal ganglia). In the absence of excitation from the subthalamic nucleus, the internal pallidum no longer suppresses unwanted movements. It is as though the ‘foot’ has been taken off the ‘brake’.

Fig. 13.15 The output of the basal ganglia is inhibitory.
This simplified diagram illustrates the ‘default’ state of the basal ganglia. The internal pallidum is tonically active and powerfully inhibits nuclei in the ventral thalamus, blocking activity in thalamocortical projections that take part in basal ganglia loops. The subthalamic nucleus (which belongs to the basal ganglia) is constantly active and excites the internal pallidum, reinforcing its restraining action on the thalamus. (If the internal pallidum is a ‘brake’, then the subthalamic nucleus is a ‘foot’ on the brake pedal.)

Key Points

All basal ganglia loops arise and terminate in the frontal lobe. The frontal cortex projects to the striatum (caudate-putamen) which is the afferent or ‘input’ part of the basal ganglia.

Cortico-striatal projections terminate on the dendritic spines of medium spiny neurons and the influence of the cortical afferent is facilitated or inhibited by the nigrostriatal dopamine projection (which terminates on the shafts of dendritic spines).

The internal pallidum is the main ‘outflow structure’ of the basal ganglia and is entirely inhibitory. It exerts a powerful restraining influence on thalamocortical neurons. It is tonically active (helping to prevent unwanted thoughts and actions), and this is reinforced by constant excitatory drive from the subthalamic nucleus (which belongs to the basal ganglia).

Direct and indirect pathways

The striatum gives rise to two sets of basal ganglia connections: the direct and indirect pathways, which are both stimulated by afferent (corticostriatal) projections. Dopamine stimulates striatal neurons belonging to the direct pathway, but at the same time inhibits those of the indirect pathway. This is because the two types of neuron express different dopamine receptors. There are five main types of dopamine receptor, arranged in two groups: D1-like and D2-like (Fig. 13.16). Direct pathway neurons are excited by dopamine since they express D1-like receptors; indirect pathway neurons are inhibited by dopamine because they express D2-like receptors (Fig. 13.17). The action of dopamine is therefore to shift the balance in favour of the direct pathway and this leads to increased activity in the SMA/motor loop.

Fig. 13.16 Dopamine receptor subtypes.
There are two major subtypes of dopamine receptor. D1-like receptors (D1, D5) are excitatory, whereas D2-like receptors (D2, D3, D4) are inhibitory.

Fig. 13.17 The effect of dopamine on a striatal medium spiny neuron depends on the type of dopamine receptor that it expresses.
Neurons that are part of the direct pathway express D1-like dopamine receptors and are excited by dopamine. Neurons that are part of the indirect pathway express D2-like dopamine receptors and are inhibited by dopamine. Dopamine therefore shifts the balance of activity in favour of the direct pathway.

Direct pathway

The internal connections of the basal ganglia work by disinhibition (release of inhibition). This happens when two inhibitory neurons are arranged in series, so that the first one inhibits the braking action of the second (illustrated in Fig. 13.18).

Fig. 13.18 The connections of the basal ganglia work by inhibition and disinhibition.
**(A)** Simple illustration of an inhibitory interaction between two nerve cells. Activity in the excitatory neuron (red) is inhibited by an inhibitory interneuron (blue); **(B)** Disinhibition (release of inhibition) occurs when two inhibitory neurons occur in sequence. In this case the excitatory neuron (red) has been released from inhibition (or ‘disinhibited’) as the neuron that was previously restraining its action has itself been inhibited. In functional terms, disinhibition is equivalent to excitation.

The arrangement of connections in the direct pathway is shown in Figure 13.19A in the context of the voluntary motor loop. Striatal neurons belonging to the direct pathway project directly to the internal pallidum and inhibit it, thereby releasing thalamocortical neurons from their normal state of inhibition. This promotes activity in the motor loop and SMA, facilitating voluntary movement.

Indirect pathway

The indirect pathway is illustrated in Figure 13.19B. Striatal neurons belonging to the indirect pathway project to the external pallidum, where they inhibit a group of cells that would normally reduce the firing rate of the subthalamic nucleus. This means that the indirect pathway disinhibits the subthalamic nucleus and accentuates its excitation of the internal pallidum. The indirect pathway therefore reinforces the ‘default’ (inhibitory) outflow of the basal ganglia. Selective loss of indirect pathway neurons leads to involuntary movements in Huntington’s disease (Clinical Box 13.8).

Clinical Box 13.8: Huntington’s disease

This is an autosomal dominant disorder with variable penetrance caused by expansion of a CAG (trinucleotide) repeat within the huntingtin gene on chromosome 4. It is therefore classified as a trinucleotide repeat expansion disorder and the number of abnormal repeats determines disease severity and age at onset. Huntington’s disease is characterized by involuntary movements with a ‘jerky’ or dance-like quality, termed chorea (Greek: khoreia, a choral dance). This is caused by selective loss of indirect pathway neurons which normally inhibit movement. Accompanying degeneration of the caudate nucleus and cerebral cortex is associated with dementia and psychiatric features (Fig. 13.20).

Fig. 13.20 Huntington’s disease.
Post-mortem examination of the brain in an individual with Huntington’s disease [right] compared to a normal control brain [left] shows marked cortical thinning, extensive loss of subcortical white matter and dilation of the lateral ventricle. There is also striking atrophy of the caudate nucleus (labelled “CN” in the normal control brain) which takes part in basal ganglia loops passing through the prefrontal cortex that are concerned with cognition and behaviour. From Kumar et al.: Robbins and Cotran’s Pathologic Basis of Disease 7e (Saunders 2004) with permission.

Key Points

The internal connections of the basal ganglia are arranged as a set of direct and indirect pathways which are both stimulated by afferent (corticostriatal) projections.

The connections of the basal ganglia work by disinhibition. Increased activity in the direct pathway disinhibits thalamocortical projection neurons by ‘switching off’ the restraining influence of the internal pallidum.

In contrast, activity in the indirect pathway disinhibits the subthalamic nucleus, which increases activity of the internal pallidum and reinforces the ‘default state’ of inhibition.

The effect of dopamine on striatal neurons depends upon the receptors that they bear. Dopamine stimulates direct pathway neurons (which have D1 receptors) but inhibits indirect pathway neurons (which have D2 receptors).

The effect of dopamine on the striatum is therefore to shift the balance in favour of the direct pathway. In the voluntary motor loop, this facilitates movement.

Basal ganglia oscillations

Some of the results of stereotactic surgery do not fit well with the direct and indirect pathway model of the basal ganglia. For instance: (i) the model does not always correctly predict the effect of focal basal ganglia lesions; and (ii) a similar effect on movement can sometimes be obtained either by stimulating or by destroying a particular structure (‘the paradox of stereotactic surgery’).

These findings may be partly explained by recordings from deep brain electrodes in experimental animals (and patients with Parkinson’s disease). These show that the basal ganglia engage in rhythmic oscillations consisting of synchronized discharges in which nuclei ‘lock step’ with one another at various frequencies:

Low frequency (<10 Hz), associated with tremor and dystonia (abnormal muscle tone and posture).

Beta band (13–30 Hz), typical of akinetic states or dopamine deficiency (e.g. in Parkinson’s disease).

Gamma band (>60 Hz), which occurs during voluntary movement and in response to dopamine replacement.

In Parkinson’s disease there is excessive beta activity, which is normalized by dopamine replacement. The effect of surgical intervention (whether by stimulation or destruction) may be to interfere with pathological oscillations, which might enable other parts of the brain to compensate. This is summarized in the idea that ‘silence is better than noise’.

Key Points

Some of the results of stereotactic surgery do not fit well with the direct and indirect pathway model of the basal ganglia (‘the paradox of stereotactic surgery’).

This may be partially explained by recordings from deep brain electrodes in experimental animals and in patients with Parkinson’s disease which show rhythmic oscillations.

Oscillations occur at characteristic frequencies, associated with: (i) tremor (<10 Hz); (ii) akinesia or dopamine deficiency (13–30 Hz); and (iii) voluntary activity or treated parkinsonism (>60 Hz).

Destruction or stimulation of various basal ganglia targets may be sufficient to disrupt pathological oscillations and allow functional compensation (‘silence is better than noise’).

Aetiology and pathogenesis

The precise cause of sporadic Parkinson’s disease is not known, but appears to be due to an interaction between genetic and environmental factors.

Risk factors

The main risk factor for Parkinson’s disease is advancing age. It is also more common in males and in people with a history of head injury. A possible link with industrialization, use of herbicides or pesticides and drinking well-water has also been described. Twin studies show a similar incidence of sporadic Parkinson’s disease in identical and fraternal twin pairs and any genetic contribution to sporadic disease is thought to be mediated by multiple (unknown) susceptibility genes.

Environmental factors

There are several examples of acquired akinetic-rigid syndromes that have features in common with idiopathic Parkinson’s disease. These are caused by various environmental, infectious or toxic agents (e.g. carbon monoxide, manganese and carbon disulphide). Parkinsonian syndromes have also been described following viral or bacterial infections (see Clinical Boxes 13.9 and 13.10).

Clinical Box 13.9: Encephalitis lethargica

In the early 20th century a viral pandemic swept across central Europe. Features included fever, headache and marked somnolence or coma caused by inflammation of the brain: encephalitis lethargica (the ‘sleepy sickness’). It affected children and young adults and carried a mortality of 40%. More than half of the survivors developed a syndrome of post-encephalitic parkinsonism and these individuals were among the first recipients of levodopa therapy in the 1960s. Post-mortem examination of the brain showed degeneration of the substantia nigra and accumulation of neurofibrillary tangles in surviving neurons, similar to those found in Alzheimer’s disease (Ch. 12).

Clinical Box 13.10: Autoimmune basal ganglia damage

The extrapyramidal movement disorder Sydenham’s chorea is characterized by ‘jerky’ involuntary limb movements (‘St Vitus’s dance’). It is now rare, but classically occurred a few weeks after recovery from rheumatic fever (caused by a streptococcal infection that affects the heart and joints). There is also a group of conditions referred to as PANDAS (paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection). Affected children may develop tics, features of obsessive-compulsive disorder (see Ch. 3, Clinical Box 3.10) or Tourette’s syndrome. The underlying cause in both disorders is autoimmune CNS damage due to ‘cross-reaction’ with a basal ganglia surface antigen that is similar to one present on the streptococcal bacterium. Interestingly, adults with OCD and related disorders are significantly more likely to show serological evidence of a previous streptococcal infection than controls.

Frozen addict syndrome

The most informative acquired parkinsonian syndrome occurred in a group of heroin addicts in California in 1982. These individuals developed an akinetic-rigid syndrome within days of injecting a synthetic heroin derivative, contaminated by the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This had been inadvertently produced during the illegal manufacture of MPPP (1-methyl-4-phenyl-4-propionoxypiperidine), a heroin analogue related to the opiate analgesic pethidine (called meperidine in the USA). MPTP-induced parkinsonism is a reliable and reproducible model of Parkinson’s disease and is now the primary non-human primate model of this condition. It also demonstrates conclusively that parkinsonism can be caused by an environmental agent.

Key Points

There are several examples of acquired akinetic-rigid disorders caused by an environmental agent (e.g. carbon monoxide, manganese, carbon disulphide) or a virus (e.g. post-encephalitic parkinsonism).

Autoimmune-mediated basal ganglia damage may also occur following infection with particular types of streptococcal bacteria (e.g. Sydenham’s chorea and PANDAS).

The most informative acquired akinetic-rigid syndrome is frozen addict syndrome, caused by accidental exposure to the neurotoxin MPTP in a group of heroin addicts in the 1980s.

MPTP in animal models

Administration of MPTP to non-human primates causes selective damage to the dopaminergic neurons of the substantia nigra and to the nigro-striatal pathway, with profound reduction of striatal dopamine. This leads to an akinetic-rigid syndrome similar to Parkinson’s disease.

Mechanism of MPTP toxicity

MPTP crosses the blood–brain barrier where it is taken up by neurons and astrocytes and metabolized by monoamine oxidase (MAO) to form MPP+ (1-methyl-4-phenylpyridinium) (Fig. 13.21A). This molecule is a highly reactive free radical species with an unpaired electron and is similar to the neurotoxic herbicide paraquat (Fig. 13.21B). MPP+ is taken up by dopaminergic neurons (via a specific monoamine transporter) where it binds to neuromelanin and becomes concentrated. MPP+ has been shown to inhibit complex I of the mitochondrial respiratory chain, leading to oxidative stress in dopaminergic neurons.

Fig. 13.21 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
**(A)** MPTP is converted to the neurotoxic agent MPP+ by monoamine oxidase B. MPP+ is then taken up by dopaminergic neurons; **(B)** MPP+ is structurally similar to the neurotoxic herbicide paraquat.

Mitochondria and oxidative stress

Inhibition of complex I of the mitochondrial electron transport chain (NADH dehydrogenase) is a key event in the pathogenesis of Parkinson’s disease. This reduces ATP production and impairs energy-dependent cellular processes. It also leads to the generation of free radicals, causing additional oxidative stress and lowering the threshold for apoptosis (programmed cell death; see Ch. 8).

Animal models using toxins such as MPTP or paraquat (or the pesticide rotenone, another complex I inhibitor) cause selective nigral degeneration and parkinsonism but lack pathological inclusions. However, Lewy bodies are produced in chronic, low-grade toxicity models, mimicking the core features of idiopathic Parkinson’s disease.

There is evidence of reduced complex I function (in brain tissue, muscle and platelets) in patients with Parkinson’s disease. Markers of oxidative stress have also been found in post-mortem studies, such as increased lipid peroxidation of cell membranes. The role of mitochondrial dysfunction and complex I inhibition is further supported by the existence of autosomal recessive forms of familial Parkinson’s disease caused by loss-of-function mutations affecting proteins that protect against oxidative stress or mitochondrial dysfunction (e.g. DJ1, PINK1).

Key Points

Inhibition of complex I of the mitochondrial respiratory chain is a key event in the pathogenesis of Parkinson’s disease and underlies MPTP-induced parkinsonism.

Administration of MPTP to non-human primates selectively damages dopaminergic neurons of the substantia nigra and causes an akinetic-rigid syndrome similar to Parkinson’s disease.

MPTP crosses the blood–brain barrier and is metabolized by monoamine oxidase to MPP+. This is a highly reactive free radical species that resembles the neurotoxic herbicide paraquat and is taken up by dopaminergic neurons, leading to mitochondrial dysfunction.

Mitochondrial dysfunction impairs energy-dependent cellular processes and leads to generation of free radicals, creating oxidative stress.

Protein aggregation

A pathological hallmark of Parkinson’s disease is aggregation of alpha-synuclein protein to form Lewy bodies. Excessive production of alpha-synuclein is known to be a factor in some familial forms of Parkinson’s disease (e.g. with duplication or triplication of the synuclein gene) and this presumably overloads protein disposal mechanisms.

Neurotoxicity of alpha-synuclein

It is not clear whether or not Lewy bodies are neurotoxic and it may be that an intermediate oligomeric species (formed during their synthesis) is responsible for damaging the cell. It has been shown that monomers of alpha-synuclein associate with cell membranes and form ring-like oligomeric assemblies with a central pore that can perforate the cell membrane. This is similar to the membrane attack complex of the complement cascade and enables free calcium to enter the cell (a final common pathway in neuronal cell death; see Ch. 8). A similar mechanism has been postulated for amyloid beta toxicity in Alzheimer’s disease (Ch. 12).

Inclusion bodies may also trigger free radical stress, either in response to the aggregated insoluble protein or as a result of mitochondrial dysfunction. Protein aggregation may reduce activity in the ubiquitin-proteasome system, either by overloading/blocking it or as a secondary consequence of oxidative stress or mitochondrial dysfunction (since it is an active, energy-dependent process; see below).

Abnormal phosphorylation

Abnormal protein phosphorylation may also be a factor in the pathogenesis of Parkinson’s disease (analogous to hyperphosphorylation of tau in Alzheimer’s disease). This is in line with some inherited forms of Parkinson’s disease in which kinase dysfunction is implicated (e.g. mutations of PINK1 or LRRK2). In particular, it has been shown that post-translational modification of serine residue 129 in the alpha-synuclein protein promotes fibril formation (native alpha-synuclein is not phosphorylated).

Dysfunction of the ubiquitin-proteasome system

The ubiquitin-proteasome system (UPS) is an important cellular mechanism for the disposal of abnormal or misfolded proteins, particularly when attempts to deal with them have failed (e.g. the unfolded protein response or upregulation of molecular chaperones, see Ch. 8).

Evidence implicating UPS dysfunction in Parkinson’s disease includes the recognition that Parkin is an E3 ubiquitin ligase that is involved in tagging abnormal proteins for proteasomal destruction. Similarly, mutations of the gene encoding UCH-L1 (ubiquitin C-terminal hydrolase L1), an enzyme involved in ubiquitin recycling, are responsible for some forms of familial Parkinson’s disease.

Importantly, proteasome dysfunction may interact with both protein aggregation and mitochondrial stress since: (i) excessive quantities of abnormal protein overwhelm cellular disposal mechanisms; and (ii) mitochondrial dysfunction leads to reduced cellular ATP, which has a negative impact on the proteasome (since it requires ATP to function).

Key Points

A hallmark of Parkinson’s disease is aggregation of alpha-synuclein (in the form of Lewy bodies) in the brain stem, cerebral hemispheres and autonomic nervous system.

It is not certain if Lewy bodies are themselves neurotoxic, but oligomers of alpha-synuclein can form pores that are able to perforate the neuronal membrane.

Pathological aggregates of insoluble protein are also likely to cause free radical stress which may in turn impair the function of mitochondria and the ubiquitin-proteasome system.

UPS-dysfunction has been demonstrated in a number of neurodegenerative diseases, including two forms of autosomal recessive parkinsonism (caused by mutations affecting Parkin and UCH-L1 proteins). Importantly, this may interact with both mitochondrial stress and protein aggregation.

Interaction of pathogenetic mechanisms

Sporadic Parkinson’s disease is thought to be caused by a combination of environmental and constitutional factors. There are three main elements (illustrated in Figure 13.22):

Fig. 13.22 Pathogenetic factors in idiopathic Parkinson’s disease.
Interaction between the three main factors creates a vicious cycle in dopaminergic neurons (ROS = reactive oxygen species).

Mitochondrial compromise, with complex I inhibition, reduced cellular ATP production, increased oxidative stress and lowered threshold for programmed cell death.

Protein aggregation, with generation of toxic oligomeric species, increased oxidative stress, secondary mitochondrial dysfunction and overload of protein disposal mechanisms.

Ubiquitin-proteasome dysfunction, with accumulation of misfolded proteins leading to Lewy body formation, exacerbated by reduced mitochondrial function and ATP depletion.

Exposure to a relevant environmental or toxic factor in a genetically predisposed individual (e.g. with reduced capacity to deal with oxidative stress, mitochondrial dysfunction or to handle misfolded proteins) is thought to trigger a set of events that culminates in a vicious cycle incorporating these three key pathogenetic elements. This occurs on a background of variable nigral reserve capacity and normal age-related degeneration (in some cases with additional contributory factors, such as head injury).

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