Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal progressive degenerative disorder of motor neurons that overlaps with frontotemporal lobar degeneration (FTLD) clinically, morphologically, and genetically. Although many distinct mutations in various genes are known to cause amyotrophic lateral sclerosis, it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Many of the gene mutations are in proteins that share similar functions. They can be grouped into those associated with cell axon dynamics and those associated with cellular phagocytic machinery, namely protein aggregation and metabolism, apoptosis, and intracellular nucleic acid transport. Analysis of pathways implicated by mutant ALS genes has provided new insights into the pathogenesis of both familial forms of ALS (fALS) and sporadic forms (sALS), although, regrettably, this has not yet yielded definitive treatments. Many genes play an important role, with TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and most importantly, C9orf72 being critical genetic players in these neurological disorders. In this mini-review, we will focus on the molecular mechanisms of these two diseases.
Highlights
TAR DNA binding protein (TARDBP) mutations are rare in Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (
Mutations in several autophagy genes have been associated with ALS, including Sequestosome 1 (SQSTM1), Superoxide Dismutase 1 (SOD1), optineurin (OPTN), valosin-containing protein (VCP), ubiquitin-2 (UBQLN2), and TANK-binding kinase 1 (TBK1) [55]
Mutations that occur in these domains (LCD and nuclear localization sequence (NLS)) can trigger the same pathological cascade, which leads to a deterioration in the dynamics of stress granules
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Many studies have shown clinical, pathological, and genetic commonalities between them They are considered two manifestations of one disease continuum, i.e., the ALS-FTD spectrum or the FTD-ALS spectrum with the broader name, i.e., frontotemporal lobar degeneration, being associated with motor neuron disorders (FTLD-MND) [11]. ALS shares a common molecular etiology with frontotemporal dementia (FTD) [17], and approximately 15% of FTD patients develop motor neuron disease (MND), and up to 50% of MND show either direct signs of cognitive impairment [18,19] or minimal-mild disturbances in executive function [20,21] These diseases are the extremes on a spectrum of clinically, pathologically, and genetically overlapping disorders [22], which suggests an overlap of disease mechanisms [23]
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