Cellular mechanisms of neurological disease

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Cellular mechanisms of neurological disease

The nervous system is subject to the full range of pathological processes found in other organs, together with a number of unique degenerative and demyelinating diseases. The basic pathological processes underlying these disorders will be discussed in this chapter (including inflammation, gliosis and neuronal cell death) before moving on to specific examples of neurological disorders in the chapters that follow. Demyelination is discussed separately in Chapter 14, in the context of multiple sclerosis.

Neuronal injury and death

Nerve cells have a limited capacity to withstand pathological stimuli. Cell death occurs when the neuron reaches a ‘point of no return’ following irreversible damage to the plasma membrane, nuclear DNA or mitochondria. Since neurons are post-mitotic cells (meaning that they are unable to divide) they cannot usually be replaced in most parts of the brain and spinal cord. Exceptions include the hippocampus and olfactory bulb (where neurons can be replenished from a pool of stem cells). The two main forms of cell death are illustrated in Figure 8.1 and discussed below.

Many components of the caspase cascade converge on the effector (or executioner) proteins, such as caspase-3, which can be used as a marker of apoptosis. Programmed cell death can be triggered by extrinsic or intrinsic stimuli.

Extrinsic pathway (Fig. 8.2)

Apoptosis can be triggered by cell death ligands in the extracellular fluid. These act on cell-surface receptors belonging to the tumour necrosis factor (TNF) family. After ligand binding, death receptors cluster within the membrane to form trimers and a conformational change in the cytoplasmic part of the protein exposes an ominously named death domain. The intracellular region of the cell death receptor binds apoptotic proteins in the cytoplasm via adaptor proteins. The interaction is mediated by death effector domains (DEDs) that are present in both the adaptor proteins and the procaspases. These interactions lead to formation of a death-inducing signalling complex (DISC) which activates caspase-8 and thereby initiates programmed cell death.

Fig. 8.2 The extrinsic pathway for apoptosis is triggered by cell death ligands binding to receptors at the cell surface.
This leads to activation of caspase-8 within the cell, which initiates apoptosis.

Intrinsic pathway (Fig. 8.3)

Apoptosis can also be triggered from within the cell if it is exposed to excessive pathological stress. Activation of the intrinsic pathway depends upon the balance of pro-apoptotic and anti-apoptotic factors, many of which are members of the BCL (B-cell lymphoma) family of proteins. Members that tend to oppose programmed cell death include Bcl-2 and Bcl-XL; others, such as Bad and Bax are pro-apoptotic. These molecules act as stress sensors in the cytoplasm, responding to pathological stimuli by translocating to mitochondria.

Fig. 8.3 The intrinsic pathway for apoptosis depends upon the balance of pro-apoptotic and anti-apoptotic members of the Bcl-2 family.
A key event is formation of the permeability transition pore (shown here in orange) in the mitochondrial membrane (coloured purple). This allows apoptosis-inducing factors to be released into the cytoplasm.

A key event is formation of a permeability transition pore (PTP) in the mitochondrial membrane, which is a large transmembrane pore (or ‘megachannel’). Pore formation allows cytochrome c oxidase and apoptosis inducing factor (AIF) to escape from mitochondria and reach the cytoplasm. Cytochrome c then forms a complex with Apaf-1 (apoptotic protease activating factor 1) which recruits caspase-9 to form a larger multi-protein complex called the apoptosome. Following formation of the apoptosome, caspase-9 is activated and apoptosis is triggered, culminating in the upregulation of cell death genes.

Disposal of the cell

Once a cell is committed to programmed cell death, its DNA and cytoskeleton are dismantled in an orderly manner. This is an active process that expends energy. A key step is activation of the enzyme caspase-activated DNAse (CAD) by effector caspases, which breaks down the DNA into nucleosomal units. Organelles are packaged into membrane-bound apoptotic bodies (see Fig. 8.1) which contain viable mitochondria. These structures express cell-surface markers that trigger their internalization by neighbouring cells. An example is the membrane constituent phosphatidylserine, which translocates from the inner to the outer leaflet of the plasma membrane. Phagocytes recognize and bind these molecules and internalize the apoptotic bodies for degradation. The entire process is carefully orchestrated and, in contrast to necrosis, there is no inflammatory reaction.

Key Points

The two main types of cell death are necrosis and apoptosis.

Necrotic cell death is characterized by dissolution of the cell with release of lysosomal enzymes and an inflammatory reaction. Liquefactive necrosis is the most common type in the CNS.

Apoptosis is the best-understood form of programmed cell death. It is triggered by extrinsic (cell death) and intrinsic (cell stress) pathways and mediated by initiator and executioner caspases.

Programmed cell death is important in embryogenesis, tumour prevention, deletion of self-reactive (autoaggressive) lymphocytes and destruction of virus-infected cells.

It also contributes to nerve cell loss in a range of neurological disorders including neurodegenerative diseases, stroke and multiple sclerosis.

Axonal damage

It is possible for axons to undergo selective degeneration without death of the cell body. For instance, following transection of a peripheral nerve, the distal portions of the affected axons degenerate together with their myelin sheaths. This is termed Wallerian degeneration, which is accompanied by regenerative changes in the parent cell, called the axon reaction. These include swelling of the cell body, dispersal of the Nissl substance (chromatolysis) and displacement and enlargement of the nucleus, reflecting increased gene transcription and protein synthesis. If the regenerative attempt fails (which is usually the case in the CNS) then the parent cell will eventually undergo apoptosis.

Transneuronal degeneration (Fig. 8.4)

Following axonal transection, neuronal degeneration may spread to involve other nerve cells, referred to as transneuronal degeneration. For instance, following interruption of an anatomical pathway consisting of a linear chain of neurons, there may be subsequent loss of nerve cells ‘downstream’ (anterograde) or ‘upstream’ (retrograde) of the original injury, which may take months or years. This reflects the general principle that nerve cells need to be integrated into a functional network and receive trophic signals from other neurons in order to remain viable.

Fig. 8.4 Degeneration following axonal injury.
Following axonal transection (neuron 2) the distal part of the nerve fibre undergoes Wallerian degeneration. Other neurons may subsequently be lost in an anatomical pathway by transneuronal degeneration (neurons 1 and 3).

Axonal regrowth

Axons are able to regenerate following peripheral nerve damage and may re-establish connections with muscle fibres or glands. The distal tips of the severed axons form growth cones (Fig. 8.5) which ‘crawl’ along residual Schwann cell basement membranes to reinnervate target structures. This process occurs after peripheral nerve injury (see Clinical Box 8.1) but does not seem to be possible in the brain and spinal cord.

Clinical Box 8.1: Bell’s palsy

Bell’s palsy is a unilateral facial paralysis caused by inflammation of the facial nerve. The cause is uncertain, but it may be related to a virus infection. Presentation is abrupt and is sometimes preceded by otalgia (earache). Damage to the facial nerve may lead to changes in the sense of taste or sensitivity to loud noises. This is because the facial nerve also supplies taste buds in the anterior two thirds of the tongue and the stapedius muscle, which prevents excessive vibration of the ear drum. In most cases symptoms improve spontaneously as the damaged axons slowly grow back. Recovery is often imperfect, with aberrant reinnervation of muscles and glands, leading to symptoms such as eye closure on attempting to smile or crocodile tears in place of salivation.

Key Points

Axonal transection leads to degeneration of the distal portion of the axon, together with its myelin sheath (termed Wallerian degeneration).

The axon reaction (in the cell body) reflects an attempt by the cell to regrow the axon and establish new connections with the denervated target structures

Axonal regrowth is commonly seen following peripheral nerve injury, but does not occur in the brain or spinal cord.

Interruption of an anatomical pathway may lead to subsequent degeneration in nerve cells proximal or distal to the original lesion (termed transneuronal degeneration).

Cell death mechanisms

Cells are continuously subjected to physiological and pathological stimuli to which they must adapt in order to survive. Pathological stimuli leading to neuronal cell death include excitotoxicity and oxidative stress, with accumulation of excessive intracellular free calcium as a final common event.

Excitotoxicity

Excessive stimulation by excitatory neurotransmitters (such as glutamate) can cause neuronal cell death in a process known as excitotoxicity. Intense glutamatergic stimulation leads to prolonged neuronal depolarization, lifting the magnesium blockade of NMDA (N-methyl D-aspartate) receptors. In this situation, free calcium ions are able to flood the neuronal cytoplasm via liberated NMDA receptors, as well as via calcium-permeable AMPA (alpha-amino, 3-hydroxy-4-isoxasole-propionic acid) receptors and voltage-gated calcium channels (see Ch. 7). This leads to further depolarization, with additional glutamate release, generating a vicious cycle. In addition to acute excitotoxic injury, there is evidence that low-grade excitotoxicity may cause chronic neuronal damage in some disorders (e.g. motor neuron disease; see Ch. 4, Clinical Box 4.9). Accumulation of intracellular free calcium is an important final common event in excitotoxicity neuronal cell death.

The role of calcium

The free calcium ion concentration in the cytoplasm is normally kept very low by several mechanisms including sequestration by calcium-binding proteins (e.g. parvalbumin and calbindin) and export from the cell. The high calcium influxes generated by excitotoxic stimulation overwhelm buffering and extrusion mechanisms, leading to activation of harmful calcium-dependent enzymes, including:

Calpains, which degrade the neuronal cytoskeleton.

Proteases, which digest structural proteins and enzymes.

Phospholipases, which impair the integrity of cell membranes.

Endonucleases, leading to DNA fragmentation.

Several pro-apoptotic genes are also upregulated by calcium-mediated cascades, which promotes degradation of the cytoskeleton and may initiate programmed cell death. Calcium-mediated activation of xanthine oxidase and nitric oxide synthase may also lead to oxidative stress.