Divergence, Convergence, and Therapeutic Implications: A Cell Biology Perspective of C9ORF72-ALS/FTD.

Molecular Neurodegeneration
Xiaoqiang TangKe Zhang

Abstract

Ever since a GGGGCC hexanucleotide repeat expansion mutation in C9ORF72 was identified as the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), three competing but nonexclusive hypotheses to explain how this mutation causes diseases have been proposed and are still under debate. Recent studies in the field have tried to understand how the repeat expansion disrupts cellular physiology, which has suggested interesting convergence of these hypotheses on downstream, functional defects in cells, such as nucleocytoplasmic transport disruption, membrane-less organelle defects, and DNA damage. These studies have not only provided an integrated view of the disease mechanism but also revealed novel cell biology implicated in neurodegeneration. Furthermore, some of the discoveries have given rise to new ideas for therapeutic development. Here, we review the research progress on cellular pathophysiology of C9ORF72-mediated ALS and FTD and its therapeutic implication. We suggest that the repeat expansion drives pathogenesis through a combination of downstream defects, of which some can be therapeutic targets.

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Citations

Aug 5, 2020·Acta Neuropathologica·Alexander BamptonAriana Gatt
Dec 29, 2020·Frontiers in Cell and Developmental Biology·Mengxi NiuYun-Wu Zhang
Apr 16, 2021·Frontiers in Neurology·Matt KeonNitin K Saksena
Jul 30, 2021·Cellular and Molecular Life Sciences : CMLS·Francesco LiguoriCinzia Volonté
Apr 30, 2021·G3 : Genes - Genomes - Genetics·Marko MelnickMercedes Prudencio

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Methods Mentioned

BETA
nucleotide exchange
GTPases
antisense oligonucleotides
SMA

Clinical Trials Mentioned

NCT02623699
NCT03626012
NCT04220021
NCT03945279

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