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Molecular biology of amyotrophic lateral sclerosis: insights from genetics

Key Points

  • Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons for which there is no therapeutic treatment currently available. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord, leading to the paralysis of voluntary muscles.

  • Most cases of ALS are classed as sporadic ALS. However, 10% of cases are inherited (known as familial ALS). The causes of most cases of ALS are as yet undefined, but investigations have identified multiple perturbations of cellular function in ALS motor neurons, including excessive excitatory tone, protein misfolding, impaired energy production, abnormal calcium metabolism, altered axonal transport and the activation of calcium-activated proteases and nucleases.

  • Five Mendelian gene defects have been reported to cause ALS. The protein products of these mutated genes are cytosolic Cu/Zn superoxide dismutase (SOD1), alsin, senataxin, VAMP (vesicle-associated membrane protein)-associated protein B and dynactin. Defects in two mitochondrial genes have been shown to also cause motor neuron disorders with clinical features that are suggestive of ALS.

  • Understanding of the pathobiology of ALS is based largely on studies of ALS-associated gene mutations, with most data being derived from studies of cell death initiated by mutant SOD1, which triggers motor neuron disease through one or more toxic properties. It is thought that either the mutant protein perturbs oxygen metabolism or that the mutated protein is misfolded and so conformationally unstable.

  • Another set of hypotheses propose that the conformational instability of mutant SOD1 induces the formation of harmful aggregates. It has been proposed that these inclusions could both mediate oxyradical chemistry and overwhelm the proteasome. The latter is predicted to impair protein degradation and recycling and to lead to the sequestration of proteins that are crucial for cellular processes.

  • Apoptosis is also thought to have a role in ALS. Reports suggest that SOD1 mutations transform SOD1 from an anti- to a pro-apoptotic protein. Cultured neuronal cells either transfected or microinjected with mutant SOD1 cDNAs die by apoptosis.

  • Disruption of other cellular processes has also been implicated in the pathogenesis of ALS, including dysfunction of mitochondria, altered axonal transport, and enhanced glutamate sensitivity and activation of the machinery of programmed cell death. Moreover, non-neuronal cells are thought to affect ALS pathogenesis through their function as modulators of neuron death.

Abstract

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by motor neuron degeneration. Mutations in more than 50 human genes cause diverse types of motor neuron pathology. Moreover, defects in five Mendelian genes lead to motor neuron disease, with two mutations reproducing the ALS phenotype. Analyses of these genetic effects have generated new insights into the diverse molecular pathways involved in ALS pathogenesis. Here, we present an overview of the mechanisms for motor neuron death and of the role of non-neuronal cells in ALS.

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Figure 1: Models of mutant SOD1-mediated toxicity.
Figure 2: Mutant SOD1 impairs multiple cellular functions.
Figure 3: The mitochondrion as a target of mutant SOD1.
Figure 4: Axonal transport is abnormal in ALS.

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Acknowledgements

The authors wish to acknowledge the following for generous support of ALS research: Al-Athel ALS Research Foundation, ALS Association, ALS Therapy Alliance, Angel Fund, Muscular Dystrophy Association, National Institutes of Health (National Institute of Neurological Disorders and Stroke, National Institute on Aging), Pierre L. de Bourgknecht ALS Foundation, Pape Adams Foundation, Project ALS and Spinal Cord Research Foundation.

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Human gene defects that cause motor neuron dysfunction. (PDF 222 kb)

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DATABASES

OMIM

Amyotrophic lateral sclerosis

Huntington's disease

SMARD

FURTHER INFORMATION

ALS Online Database

Glossary

Orphan disease

A condition that affects fewer than 200,000 people nationwide.

Fasciculation

A muscle contraction visible under the skin that represents the spontaneous firing of a single motor neuron and, as a result, of all the muscle fibres it innervates.

Spasticity

Persistent muscle contraction that causes stiffness and interferes with gait, movements and speech.

Bunina bodies

Characteristic proteinacious inclusions in ALS motor neurons.

Ubiquitin

A ubiquitous protein present in all eukaryotes (but absent from prokaryotes). As part of the ubiquitin–proteasome complex, ubiquitin binds and labels proteins to be proteolytically digested and removed from the cell. The ubiquitin–proteasome system is essential for many cellular processes, including cell cycling, signal transduction and the regulation of gene expression.

Guanine nucleotide exchange factor

(GEF). A protein that mediates the exchange of GDP to GTP, catalysed by a GTP-binding protein.

GTPases

A large family of enzymes that bind and hydrolyse GTP.

Endosome

A membrane-bound, intracellular oganelle. Endocytotic vesicles derived from the plasma membrane are actively transported to fuse with endosomes; endosomes also fuse with vesicles of the endoplasmic reticulum that contain newly expressed proteins.

Dynein

A motor protein that converts the chemical energy of ATP into mechanical energy for movement. Dynein transports several cellular cargos along the microtubules.

BCL2

The founding member of a family of apoptosis-regulating proteins. Many BCL2 family members regulate mitochondria-dependent steps in cell death pathways, with some suppressing and others promoting the release of apoptogenic proteins from these organelles.

Apoptosis

A mode of cell death in which the cell triggers its own destruction by activating pre-programmed intracellular suicide machinery.

Caspases

A family of intracellular cysteine endopeptidases that have a key role in mammalian apoptosis. They cleave proteins at specific aspartate residues.

Astrogliosis

Proliferation and ramification of glial cells in response to brain damage.

Microgliosis

Proliferation and activation of microglial cells, which are the primary immune effector cells in the brain.

Kinesins

A class of motor proteins that attach to microtubules and transport vesicles along the tubule.

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Pasinelli, P., Brown, R. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 7, 710–723 (2006). https://doi.org/10.1038/nrn1971

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