Journal Article

Molecular biology of amyotrophic lateral sclerosis: insights from genetics

Brown, Robert H., Pasinelli, Piera

2006

Overview

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. Mutations in proteins essential for certain cellular processes have been implicated in motor neuron degeneration in ALS. Pasinelli and Brown review how genetic analyses of these effects are unravelling the diverse molecular pathways involved in ALS pathogenesis. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - physiopathology / Animal Genetics and Genomics / Animals / Apoptosis - genetics / Behavioral Sciences / Biological and medical sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Central Nervous System - metabolism / Central Nervous System - pathology / Central Nervous System - physiopathology / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Dementia / Fundamental and applied biological sciences. Psychology / General aspects / Genes / Genetic Predisposition to Disease - genetics / Humans / Medical sciences / Mitochondria - genetics / Mitochondria - metabolism / Mitochondrial DNA / Muscle contraction / Mutation - genetics / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Neurobiology / Neurology / Neurons / Neurosciences / Paralysis / Proteins / Psychology. Psychoanalysis. Psychiatry / Psychology. Psychophysiology / review-article / Signal transduction / Signal Transduction - genetics / Superoxide Dismutase - genetics / Superoxide Dismutase - metabolism / Superoxide Dismutase-1