Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion.

Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion. Behav Neurol. 2019;2019:2909168 Authors: Babić Leko M, Župunski V, Kirincich J, Smilović D, Hortobágyi T, Hof PR, Šimić G Abstract Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2-10 hexanucleotide GGGGCC repeats in the C9orf72 gene, while more than a few hundred repeats represent a risk for ALS and FTD. The proposed molecular mechanisms by which C9orf72 repeat expansions induce neurodegenerative changes are C9orf72 loss-of-function through haploinsufficiency, RNA toxic gain-of-function, and gain-of-function through the accumulation of toxic dipeptide repeat proteins. However, many more cellular processes are affected by pathological processes in C9FTD/ALS, including nucleocytoplasmic transport, RNA processing, normal function of nucleolus, formation of membraneless organelles, translation, ubiquitin proteasom...
Source: Behavioural Neurology - Category: Neurology Authors: Tags: Behav Neurol Source Type: research