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 proteasome system, Notch signalling pathway, granule transport, and normal function of TAR DNA-binding protein 43 (TDP-43). Although the exact molecular mechanisms through which C9orf72 repeat expansions account for neurodegeneration have not been elucidated, some potential therapeutics, such as antisense oligonucleotides targeting hexanucleotide GGGGCC repeats in mRNA, were successful in preclinical trials and are awaiting phase 1 clinical trials. In this review, we critically discuss each proposed mechanism and provide insight into the most recent studies aiming to elucidate the molecular underpinnings of C9FTD/ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two clinically distinct entities
FTD patients are divided in three clinical syndromes according to their symptomatology: two language variants (progressive nonfluent aphasia (PNFA) and semantic dementia (SD)), and behavioral variant of frontotemporal dementia [3]
It was later shown that the mutation is an expansion of GGGGCC (G4C2) hexanucleotide repeat in a noncoding region of the chromosome 9 open reading frame 72 (C9orf72) gene [14,15,16], which is the most common genetic cause of ALS and FTD in certain populations
Summary
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two clinically distinct entities. The disease onset is mostly after 60 years of age with a prevalence of around 5 cases per. Be one of the most common forms of dementia in the population under 65 years of age with the prevalence around 10 cases per 100,000 [4]. FTD patients are divided in three clinical syndromes according to their symptomatology: two language variants (progressive nonfluent aphasia (PNFA) and semantic dementia (SD)), and behavioral variant of frontotemporal dementia (bvFTD) [3]. Genetic, and neuropathological overlap between ALS and FTD, these two diseases are considered as two extremes of the FTD/ALS spectrum (Figure 1) [1]. About 15% of FTD patients show symptoms of ALS, and up to 50% of ALS patients have symptoms of FTD [5]
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