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From charcot to lou gehrig: deciphering selective motor neuron death in als

Abstract

Since its description by Charcot more than 130 years ago, the mechanism underlying the characteristic selective degeneration and death of motor neurons in amyotrophic lateral sclerosis has remained a mystery. Modern genetics has now identified mutations in two genes — SOD1 and ALS2 — as primary causes of the disease, and has implicated others as potential contributors. Insights into these abnormalities, together with errors in the handling of synaptic glutamate and the potential excitotoxic response that this alteration provokes, have provided leads for the development of new strategies to identify an as yet elusive remedy for this progressive, fatal disorder.

Key Points

  • The most common motor neuron disease in adults is amyotrophic lateral sclerosis (ALS). The primary hallmark of ALS is selective killing of motor neurons, which initiates, in mid-life, a progressive paralysis. The causes of almost all occurrences of the disease remain unknown. Most instances do not have any apparent genetic linkage (sporadic ALS), but the disease is inherited in a dominant manner in the remaining 5–10% of cases (familial ALS). Four principal ideas have been put forward to account for motor neuron death in ALS: oxidative damage, axonal strangulation from the disorganization of neurofilaments, toxicity from intracellular aggregates and/or a failure of protein folding, and excitotoxic death arising from the mishandling of glutamate.

  • The idea that oxidative damage is involved in ALS was prompted by the discovery that mutations in superoxide dismutase 1 (SOD1) are a primary cause of the disease. However, changes in dismutase activity do not explain cell death; rather, the mutations confer SOD1 with toxic properties.

  • An involvement of axonal strangulation is supported by the abnormal accumulation of neurofilaments in cases of sporadic and familial ALS. Deficits in slow axonal transport arise early on in ALS, and neurofilament mutations can be direct causes of motor neuron death in mice.

  • The presence of intracellular aggregates is a common feature of familial ALS. It has been proposed that these aggregates might be toxic, and that toxicity might arise from protein misfolding mediated by mutant SOD1. The mutant SOD1 chronically ties up chaperones that are needed for catalysing the folding of other proteins, whereas ubiquitin-mediated protein degradation might be choked by those same aggregates.

  • Repetitive motor neuron firing can lead to excitotoxic death if glutamate release is not handled properly at the dendrites of upper and lower motor neurons. Indeed, ALS has been associated with reductions in the level of glial glutamate transporters. This defect might lead to the abnormal accumulation of the neurotransmitter glutamate and to glutamate-mediated neuronal death.

  • Molecular genetics in mice have highlighted the selective sensitivity of motor neurons to minor disturbances in the induction of vascular endothelial cell growth factor (VEGF). So, mice that lack the ability to induce the expression of VEGF when oxygen levels are low show ALS-like neuropathology. VEGF might act directly on motor neurons as a neurotrophic factor, or might act instead by regulating blood supply to motor neurons.

  • Recently, a second gene relevant to ALS — a putative guanine exchange factor for a G protein that is unknown at present — has been identified. Mutations of this gene, termed ALS2, provoke an early-onset, recessive, slowly progressing form of ALS.

  • Many different drugs have been tested to try to alleviate the symptoms of patients with ALS, but none has proved to be effective. Our more recent insights into the mechanisms of this disease are already guiding the exploration for potential new treatments, including growth factors, regulators of glutamate-mediated transmission and stem cell therapies.

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Acknowledgements

We thank J. Liu and A. Hirano for kindly providing part b of figure 1 and part a of figure 4, respectively.

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Correspondence to Don W. Cleveland.

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Glossary

SPASTICITY

The persistent contraction of certain muscles, which causes stiffness and interferes with gait, movement or speech.

NEUROFILAMENT

A type of intermediate filament that is found only in neurons and serves as a cytoskeletal element that supports the axonal cytoplasm.

GUANINE EXCHANGE FACTOR

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

FRAMESHIFT MUTATION

The addition or deletion of a nucleotide, which shifts the reading frame during translation such that the protein sequence from that point onwards is altered.

CASPASES

Cysteine proteases involved in apoptosis, which cleave at specific aspartate residues.

CHAPERONE

A protein that mediates the folding or assembly of another polypeptide, but does not form part of the completed structure, or participate in its biological function.

PROTEASOME

A protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.

CELL AUTONOMOUS

A genetic trait in which only genotypically mutant cells show the mutant phenotype. In contrast, a cell non-autonomous trait is one in which genotypically mutant cells cause other cells (regardless of their genotype) to show a mutant phenotype.

PENETRANCE

The proportion of genotypically mutant organisms that show the mutant phenotype. If all genotypically mutant individuals show the mutant phenotype, then the genotype is said to be completely penetrant.

CHARCOT–MARIE–TOOTH DISEASE

A genetic neurological disease that is characterized by the degeneration of peripheral nerves and a slowly progressive atrophy of the muscles in the foot, lower leg, hand and forearm, and a mild loss of sensation in the limbs, fingers and toes. The first sign of the disease is generally a high-arched foot and gait disturbances.

PLECKSTRIN HOMOLOGY DOMAIN

A sequence of about 100 amino acids that is present in many signalling molecules. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.

DBL HOMOLOGY DOMAIN

A sequence that is present in some guanine nucleotide exchange factors, originally identified in the protein DBL, a molecule of unknown function that was originally identified in a human diffuse B-cell lymphoma.

RHO

A Ras-related GTPase involved in controlling the polymerization of actin.

WOBBLER MOUSE

A mutant mouse that shows motor neuron degeneration and astrocyte reactivity in the spinal cord, and defects in spermatogenesis. The mutant gene has not been identified.

NEUROMUSCULAR DEGENERATION MOUSE

A mutant mouse that shows severe muscle atrophy due to progressive degeneration of spinal motor neurons. The responsible mutation has been localized to a gene known as Smbp2, which encodes a DNA-binding protein.

PROGRESSIVE MOTOR NEUROPATHY MOUSE

A mouse with an autosomal-recessive mutation that results in early-onset motor neuron disease, rapidly progressing hindlimb paralysis, severe muscular wasting and death. The mutant gene has not been identified.

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Further reading

Figure 1: ALS-causing mutations lie throughout the SOD1 polypeptide.
Figure 2: SOD1 chemistry.
Figure 3: Models for SOD1-mediated toxicity linked to altered conformation and/or aggregation of mutant SOD1 subunits.
Figure 4: Neurofilament involvement in motor neuron disease.
Figure 5: Models for the action of VEGF in supporting motor neuron survival.
Figure 6: The specificity of the toxic effect of SOD1 mutations on motor neurons arises from the convergence of several risk factors.