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Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degenerations: Similarities in Genetic Background - PubMed

  • ️Fri Jan 01 2021

Review

Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degenerations: Similarities in Genetic Background

Eva Parobkova et al. Diagnostics (Basel). 2021.

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.

Keywords: amyotrophic lateral sclerosis; frontotemporal dementia; genetics; neuropathology.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Structure of RNA-binding protein (RBP) genes.

Figure 2
Figure 2

Structure of the RBM45 gene.

Figure 3
Figure 3

ALS-related genes. Symbols: LMN: Lower motor neuropathies, FTD: Frontotemporal dementia, UMN: Upper motor neurons. X-axis: Overlap with frontotemporal dementia, Y-axis: The extent to which corticospinal versus lower motor neurons are involved (updated following Ghasemi M. 2018).

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