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.

Necrosis

Tissue death resulting from damage or disease is referred to as necrosis (Greek: nekros, corpse). This is the end-point of numerous pathological processes and has features in common with the dissolution of the body that occurs after death (autolysis). Necrosis is associated with cellular swelling, loss of membrane integrity and influx of sodium and calcium ions, with eventual rupture of the cell. This is followed by digestion of the cellular constituents by lysosomal enzymes. As the necrotic cell breaks down, its internal components are discharged into the extracellular space, eliciting an inflammatory reaction. Several patterns of necrosis are recognized, but the type usually seen in the brain is called liquefactive necrosis. In this process, dead brain tissue is gradually removed by macrophages and liquefied by hydrolytic enzymes. Complete resorption may take several years, ultimately leaving only a fluid-filled cyst.

Apoptosis

Deliberate deletion of unwanted cells is termed programmed cell death. This is essential for normal growth and development, but is also responsible for cell loss in a number of CNS pathologies including neurodegeneration, stroke and multiple sclerosis.

The most common and best characterized form of programmed cell death is apoptosis (pronounced: apa-TOSIS). The term derives from the Greek and alludes to the deliberate shedding of autumn leaves (Greek: apo, away from; ptosis, falling). Apoptosis has characteristic microscopic features including cell shrinkage, condensation of the nuclear chromatin, cytoplasmic blebbing and formation of membrane-bound apoptotic bodies which contain viable organelles.

Most newly formed nerve cells are primed to commit programmed cell death (‘cellular suicide’) unless rescued by exposure to the appropriate trophic factors (Greek: trophē, nourishment). One of the best known examples of this is the dependence of dorsal root ganglion neurons on nerve growth factor (NGF). During CNS development, up to 50% of neurons are deliberately deleted because they fail to (i) reach their intended targets or (ii) make appropriate connections with other nerve cells.

Apoptosis is also an important mechanism for the destruction of critically injured or abnormal cells and is triggered in diseases where pathological stress has compromised key cellular elements beyond repair. Irreparable damage to the nuclear DNA is a potent trigger for apoptosis, contributing to the prevention of tumours. It is also used by activated lymphocytes to sacrifice virus-infected cells and to delete self-reactive T-lymphocytes in the thymus gland (preventing autoimmune disease).

Caspases

Apoptosis is orchestrated by a family of proteolytic enzymes called caspases (cysteine-dependent aspartate-specific proteases) which cleave target proteins at aspartate residues. The caspases are synthesized as inactive procaspases and once activated are able to cleave parts of the neuronal cytoskeleton and nuclear DNA.

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.

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.

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.

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.

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.

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:

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.