Abstract
Neurodegenerative diseases share pathogenic mechanisms at the cellular level including protein misfolding, excitotoxicity and altered RNA homeostasis among others. Recent advances have shown that the genetic causes underlying these pathologies overlap, hinting at the existence of a genetic network for neurodegeneration. This is perhaps best illustrated by the recent discoveries of causative mutations for amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Once thought to be distinct entities, it is now recognized that these diseases exist along a genetic spectrum. With this wealth of discoveries comes the need to develop new genetic models of ALS and FTD to investigate not only pathogenic mechanisms linked to causative mutations, but to uncover potential genetic interactions that may point to new therapeutic targets. Given the conservation of many disease genes across evolution, Caenorhabditis elegans is an ideal system to investigate genetic interactions amongst these genes. Here we review the use of C. elegans to model ALS and investigate a putative genetic network for ALS/FTD that may extend to other neurological disorders.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting 1–2/100,000 individuals
It is hypothesized that superoxide dismutase 1 (SOD1) mutations cause toxicity through a gain of function, even though a loss of enzyme activity have been observed in patients and some models (Saccon et al, 2013)
Other models are non-neuronal in nature and have relied on the expression of SOD1 proteins in the body wall muscles where it was observed that distinct SOD1 mutations have varying propensities to aggregate (Gidalevitz et al, 2009)
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting 1–2/100,000 individuals. Most cases of ALS are sporadic, but 10% of cases are familial (Turner et al, 2013b). Mutations in the gene superoxide dismutase 1 (SOD1) were identified in 1993 (Rosen et al, 1993) as the first cause of familial ALS. Mutations in C9ORF72 have turned out to be a major cause of familial and sporadic ALS (DeJesus-Hernandez et al, 2011; Renton et al, 2011). Over the past few years, the identification of TDP-43, C9ORF72 and UBQLN2 as genes causing ALS and FTD has suggested a similarity for both diseases (Morris et al, 2012). The genes involved in ALS have diverse functions and we still do not know how they interact to cause motor neuron degeneration. The identification of biomarkers is essential for the rapid, early diagnosis of ALS, and the identification of new drugs limiting the degeneration of motor neuron is an essential unmet need for ALS patients
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