Genetics of familial and sporadic amyotrophic lateral sclerosis

Gros‐Louis, François; Gaspar, Cláudia; Rouleau, Guy A.

doi:10.1016/j.bbadis.2006.01.004

Cited by 228 publications

(166 citation statements)

References 180 publications

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“…Thus, like many other progressive neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's disease, ALS represents a largely unmet medical need (28,46,125). Studies on rare familial forms of several of these diseases have provided insights into the molecular basis of their pathogenesis (20,52,109), and are beginning to reveal a general unifying set of factors in these slowly progressing diseases. These include protein aggregation, mitochondrial injury, inflammatory response, and nitrosative and oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Carter

Anklesaria

Choi

et al. 2009

Antioxidants & Redox Signaling

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Enhanced redox-stress caused by neuroinflammation, mitochondria, and NADPH oxidases has been hypothesized to play critical roles in disease progression of amyotrophic lateral sclerosis (ALS). However, distinguishing whether the redox-stress observed in ALS is due to a primary defect in cellular reactive oxygen species metabolism=catabolism, or is a secondary consequence of neuroinflammation, has been difficult and the issue remains a matter of debate. Emerging evidence suggests that defects in genes that regulate NADPH oxidases may account for at least some forms of ALS. NADPH oxidases are key signaling complexes that influence cellular responses to growth factors and cytokines. In this context, NADPH oxidase-derived reactive oxygen species exert spatial control over the redox-dependent activation of certain pro-inflammatory receptors. Understanding the biology of how NADPH oxidases control cell signaling may help to clarify how genetic determinants of ALS lead to dysregulated pro-inflammatory signaling. This review provides a framework for understanding endosomal signaling through NADPH oxidases and potential mechanisms whereby gene defects in various forms of ALS may influence this cellular process and lead to motor neuron degeneration. Lastly, this review discusses past and current efforts to treat ALS using antioxidant therapies, as well as the limitations and advantages of each of these approaches. Antioxid. Redox Signal. 11, 1569-1586.

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Section: Introductionmentioning

confidence: 99%

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Carter

Anklesaria

Choi

et al. 2009

Antioxidants & Redox Signaling

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“…Mutations in this gene predominantly cause autosomal dominant disease and account for 20% of FALS cases. 2 Mutations in other genes cause rarer forms of ALS. These genes include Sentaxin, a DNA/RNA helicase that causes juvenile ALS, 3 Alsin, 4,5 Dynactin, 6,7 angiogenin, 8 and synaptobrevin associated membrane protein B.…”

Section: Introductionmentioning

confidence: 99%

TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

Deerlin

Leverenz

Bekris

et al. 2008

The Lancet Neurology

643

459

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“…Approximately 10% of the cases are familial, of which 20% are caused by dominantly inherited mutations in the Cu/Zn-superoxide dismutase (SOD) gene (4,5). Recently, mutations in other genes, including the human VAP-B, have been identified in ALS patients (6 -8).…”

mentioning

confidence: 99%

Structural Requirements for VAP-B Oligomerization and Their Implication in Amyotrophic Lateral Sclerosis-associated VAP-B(P56S) Neurotoxicity

Kim

Leal

Halevy

et al. 2010

Journal of Biological Chemistry

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The integral endoplasmic reticulum (ER)-membrane protein VAP-B interacts with various lipid-transfer/binding proteins containing an FFAT motif through its N-terminal MSP domain. A genetic mutation within its MSP domain, P56S, was identified in familial forms of motor neuron diseases. This mutation induces the formation of insoluble VAP-B(P56S) protein aggregates by an unknown mechanism. In this study, we defined the structural requirements for VAP-B oligomerization and demonstrated their contribution for VAP-B(P56S) aggregation and neurotoxicity. We show that the oligomerization of VAP-B is mainly mediated by its coiled-coil domain and that the GXXXG dimerization motif within the transmembrane domain mediates transmembrane domains self-association but is insufficient to drive VAP-B oligomerization. We further show that the oligomerization of the wild-type VAP-B is independent of its MSP domain. However, we found that the P56S mutation induces conformational changes within the MSP domain and facilitates its propensity to aggregate by exposing hydrophobic patches to the solvent. These conformational changes have no direct effect on FFAT binding. Rather, they enhance VAP-B(P56S) oligomerization driven by the combined contributions of the coiled-coil and the transmembrane domains, thereby preventing accessibility to FFAT-binding site, facilitating the production of VAP-B(P56S)-insoluble aggregates and consequently its neurotoxicity. These results shed light on the mechanism by which VAP-B(P56S) aggregates are formed and induce familial motor neuron diseases.Protein aggregation and inclusion body formation are common pathological features of many neurological disorders including Huntington disease, Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (ALS) 3 (1, 2).ALS is a fatal neurodegenerative disorder involving progressive loss of motor neurons in the cerebral cortex, brain stem, and spinal cord (3). Approximately 10% of the cases are familial, of which 20% are caused by dominantly inherited mutations in the Cu/Zn-superoxide dismutase (SOD) gene (4, 5). Recently, mutations in other genes, including the human VAP-B, have been identified in ALS patients (6 -8).The mutation in VAP-B substitutes a highly conserved proline residue at position 56 by a serine (P56S) and is associated with three forms of human motor neuron diseases: a late-onset spinal muscular atrophy, an atypical ALS type 8, and a typical severe ALS with rapid progression (7, 9). Atypical ALS type 8 is an autosomal dominant slowly progressive disorder characterized by fasciculation, cramps, and postural tremor. It is currently unknown how this P56S mutation induces motor neuron degeneration. Nevertheless, recent studies suggest that the VAP-B(P56S) mutant acts in a dominant fashion through dimerization with the wild-type protein and inactivating the heterodimer and that expression of the VAP-B(P56S) mutant induces the formation of insoluble protein aggregates (7, 10 -15). Indeed, co-expression studies suggest that wild-type VAP-B is...

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Genetics of familial and sporadic amyotrophic lateral sclerosis

Cited by 228 publications

References 180 publications

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

Structural Requirements for VAP-B Oligomerization and Their Implication in Amyotrophic Lateral Sclerosis-associated VAP-B(P56S) Neurotoxicity

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