Key Points
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Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders that are characterized by muscle weakness and/or spastic paralysis, which results from the selective degeneration of lower motor neurons and/or upper motor neurons, respectively.
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The MNDs currently being investigated are: amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA) and lethal congenital contracture syndrome (LCCS).
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ALS is the most common adult-onset MND 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, which leads to the paralysis of voluntary muscles.
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Family-based linkage studies have led to the identification of eight genes for ALS. The protein products of these mutated genes are superoxide dismutase 1 (SOD1), alsin, senataxin, vesicle-associated membrane protein-associated protein B (VAPB), angiogenin, dynactin, TAR DNA-binding protein 43 (TDP43) and FUS.
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Mutations in the SOD1 gene are the most common genetic cause of familial ALS and account for 15–20% of autosomal dominant familial ALS cases (1–2% of all ALS cases).
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HSPs are the second most important group of MNDs in terms of the number of mutations identified and the resulting insights into the pathogenesis of MND. The 45 spastic paraplegia loci and 20 causative genes reported so far suggest various pathogenic mechanisms, including axonal transport, membrane trafficking and mitochondrial dysfunction.
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RNA-processing defects are observed in several MNDs, and in ALS the TARDBP and FUS genes have provided direct links to defects in RNA processing as a broad pathway that contributes to motor neuron degeneration (however, this is not the case for HSP).
Abstract
The past few years have seen the identification of dozens of genes with causal roles in motor neuron diseases (MNDs), particularly for amyotrophic lateral sclerosis and hereditary spastic paraplegia. Although many additional MND genes remain to be identified, the accumulated genetic evidence has already provided new insights into MND pathogenesis, which adds to the well-established involvement of superoxide dismutase 1 (SOD1) mutations. The pathways that have been recently implicated include those that affect RNA processing, axonal transport and mitochondrial function. The functional classes of MND genes identified so far are likely to aid the selection of high-priority candidate genes for future investigation, including those for so-called sporadic cases.
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Acknowledgements
The authors wish to thank C. Vande Velde and I. A. Meijer for their careful and insightful reading of the manuscript; their ideas and suggestions were welcomed and appreciated. G.A.R. has received MND-related funding from the Canadian Institutes of Health, the Muscular Dystrophy Association ALS Division, the ALS Association and the ALS Society of Canada.
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Glossary
- Linkage study
-
A method of searching for the chromosomal location of a gene by looking for co-segregation of the disease with genetic markers of known chromosomal location within families.
- Epigenetics
-
Changes in gene expression that are stable through cell division but do not involve changes in the underlying DNA sequence. The best-studied example is cellular differentiation, but environmental factors, such as maternal nutrition, can influence epigenetic programming.
- Reactive oxygen species
-
Ions or small molecules that include oxygen ions, free radicals and peroxides, both inorganic and organic.
- Hu-antigen R
-
An RNA-stabilizing protein that is a member of the embryonic lethal abnormal visual (ELAV) family. These proteins recognize the 3′ UTR sequences of mRNAs, in particular the adenine/uridine-rich elements, the widespread occurrence of which suggests that they are involved in the regulation of many biological processes.
- Astrocyte
-
One of the three main cell types in the brain, the others being neurons and oligodendrocytes. Astrocytes act as a scaffold that maintains brain structure and they can alter the extracellular milieu and ionic concentration through the expression of various transporters and channel proteins. They support the functions of neurons and oligodendrocytes.
- Cre recombinase
-
A type I topoisomerase from the P1 bacteriophage that catalyses the site-specific recombination of DNA between loxP sites. It binds to the loxP sites to allow DNA that is cloned between the sites to be removed.
- Microglia
-
Small neuroglial cells of the central nervous system. They have long processes and ameboid and phagocytic activity at sites of neural damage or inflammation.
- Schwann cell
-
A type of non-neuronal brain cell that lacks axons and dendrites and forms axons in the peripheral nervous system.
- Microglia activation
-
Microglia can be activated by several factors, including glutamate receptor agonists, pro-inflammatory cytokines, cell necrosis factors and lipopolysaccharide. Once activated, the cells undergo key morphological changes, including the secretion of cytotoxic factors, recruitment molecules and pro-inflammatory molecules. In addition, activated microglia undergo proliferation to increase their numbers.
- Penetrance
-
The proportion of individuals with a specific genotype who manifest the genotype at the phenotypic level. If the penetrance of a disease allele is 100%, all individuals who carry that allele will express the associated disorder and the genotype is said to be 'completely penetrant'.
- Polymorphism
-
The contemporary definition is any site in the DNA sequence that is present in the population in more than one state. By contrast, the traditional definition is an allele with a population frequency of between >1% and <99%.
- Compound heterozygote
-
A situation in which an individual is heterozygous for two different mutations at the same locus.
- Proband
-
In a family study, the individual who is first identified in the family as having the disease under study.
- Heterogeneous nuclear ribonucleoprotein
-
A complex of RNA and protein that is present in the nucleus during transcription and post-transcriptional modification of pre-mRNA. Such complexes serve as a signal that the pre-mRNA is not yet fully processed and ready for export to the cytoplasm.
- Homozygosity mapping
-
An approach for detecting rare disease-promoting variants. This method detects extensive homozygous haplotypes that are hundreds of kilobases or more in length and that are unique to, or enriched in, affected individuals.
- Retrograde motor
-
Motor proteins bind and transport several different cargoes in nerve cells, including organelles, polymers and vesicles containing neurotransmitters. Retrograde transport runs towards the minus end of the axons.
- Frontal lobe
-
An area of the brain located at the front of each cerebral hemisphere that is involved in higher mental functions. The executive functions of the frontal lobe include the ability to recognize future consequences, override and suppress unacceptable social responses, and determine similarities and differences between things or events.
- Anterior temporal lobe
-
The temporal lobes are regions of the cerebral cortex that are located beneath the Sylvian fissure on both the left and right hemispheres of the brain. The anterior part of the lobes is involved in visual processing and object perception and recognition.
- Haploinsufficiency
-
A condition in a diploid organism in which a single functional copy of a gene results in a phenotype, such as a disease.
- Association studies
-
A gene-discovery strategy that compares allele frequencies in cases and controls to assess the contribution of genetic variants to phenotypes in specific populations.
- Meta-analysis
-
An approach that combines the results of several studies that address a set of related research hypotheses to overcome the problem of reduced statistical power in studies with small sample sizes.
- Population stratification
-
A population that contains several subpopulations that differ in their genetic characteristics.
- Genome-wide association studies
-
The examination of DNA variation (typically SNPs) across the whole genome in a large number of individuals who have been matched for population ancestry and assessed for a disease or trait of interest. Correlations between variants and the trait are used to locate genetic risk factors.
- Microsatellite
-
A class of repetitive DNA that is made up of repeats that are 2–8 nucleotides in length. Microsatellites can be highly polymorphic and are frequently used as molecular markers in population genetics studies.
- 1000 Genomes Project
-
An international research effort, launched in 2008, to establish by far the most detailed catalogue of human genetic variation. Plans are to sequence the genomes of at least 1,000 anonymous participants of different ethnic groups over the next 3 years using newly developed technologies.
- Copy number variant
-
A DNA sequence variant (including deletions and duplications) in which the result is a departure from the expected diploid representation of the DNA sequence.
- Balanced translocation
-
A translocation between non-homologous chromosomes in which the exchange occurs with no gain or loss of genetic material.
- Midbody
-
A transient organelle-like structure that is formed during mammalian cell division and persists until just before the complete separation of the dividing cells.
- Myelin
-
An electrically insulating material that usually forms a layer around the axon of a neuron. It is essential for the proper functioning of the nervous system. Schwann cells supply the myelin for peripheral neurons, whereas oligodendrocytes supply it to neurons of the central nervous system.
- Anterior horn
-
The ventral column of grey matter in the spinal cord that contains the cell bodies of motor (efferent) neurons.
- Cristae
-
Internal compartments that are formed by the inner membranes of mitochondria. They contain several key proteins for aerobic respiration, including ATP synthase and various cytochromes.
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Dion, P., Daoud, H. & Rouleau, G. Genetics of motor neuron disorders: new insights into pathogenic mechanisms. Nat Rev Genet 10, 769–782 (2009). https://doi.org/10.1038/nrg2680
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DOI: https://doi.org/10.1038/nrg2680
