Molecular pathology and genetic advances in amyotrophic lateral sclerosis: An emerging molecular pathway and the significance of glial pathology

Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.
Acta Neuropathologica (Impact Factor: 10.76). 11/2011; 122(6):657-71. DOI: 10.1007/s00401-011-0913-0
Source: PubMed


Research into amyotrophic lateral sclerosis (ALS) has been stimulated by a series of genetic and molecular pathology discoveries. The hallmark neuronal cytoplasmic inclusions of sporadic ALS (sALS) predominantly comprise a nuclear RNA processing protein, TDP-43 encoded by the gene TARDBP, a discovery that emerged from high throughput analysis of human brain tissue from patients with frontotemporal dementia (FTD) who share a common molecular pathology with ALS. The link between RNA processing and ALS was further strengthened by the discovery that another genetic locus linking familial ALS (fALS) and FTD was due to mutation of the fused in sarcoma (FUS) gene. Of potentially even greater importance it emerges that TDP-43 accumulation and inclusion formation characterises not only most sALS cases but also those that arise from mutations in several genes including TARDBP (predominantly ALS cases) itself, C9ORF72 (ALS and FTD cases), progranulin (predominantly FTD phenotypes), VAPB (predominantly ALS cases) and in some ALS cases with rare genetic variants of uncertain pathogenicity (CHMP2B). "TDP-proteinopathy" therefore now represents a final common pathology associated with changes in multiple genes and opens the possibility of research by triangulation towards key common upstream molecular events. It also delivers final proof of the hypothesis that ALS and most FTD cases are disorders within a common pathology expressed as a clinico-anatomical spectrum. The emergence of TDP-proteinopathy also confirms the view that glial pathology is a crucial facet in this class of neurodegeneration, adding to the established view of non-nerve cell autonomous degeneration of the motor system from previous research on SOD1 fALS. Future research into the mechanisms of TDP-43 and FUS-related neurodegeneration, taking into account the major component of glial pathology now revealed in those disorders will significantly accelerate new discoveries in this field, including target identification for new therapy.

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Available from: Janine Kirby, Jan 08, 2014
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    • "The attention on this issue arose in 2006 with the discovery of the mutations on the RNA-processing protein TDP-43, accounting for about 4% of fALS and a smaller percentage of sALS cases (Chio et al., 2012), and leading to mislocalization of the protein from nucleus to toxic cytoplasmic aggregates in both neuronal and glial cells (Arai et al., 2006; Ince et al., 2011; Neumann et al., 2006). Most importantly, it was found that non mutated TDP-43 is the major constituent of intra-nuclear and cytoplasmic neuronal inclusions of most sALS cases (Ince et al., 2011). Later on, what became clear from studies on several TDP-43 rodent models is that both loss and over expression of either wild type (WT) or mutant TDP-43 is neurotoxic, thus associating abnormal protein homeostasis with ALS (Lee et al., 2011). "
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