C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia

Abstract

Purpose of reviewThe molecular mechanisms that underlie chromosome 9 open reading frame 72 (C9orf72)-associated amyotrophic lateral sclerosis and frontotemporal dementia are rapidly emerging. Two potential disease mechanisms have been postulated – gain or loss of function. We provide an overview of recent advances that support or oppose gain-of-function and loss-of-function mechanisms.Recent findingsSince the discovery that a noncoding repeat expansion in C9orf72 was responsible for chromosome 9-linked amyotrophic lateral sclerosis and frontotemporal dementia in 2011, a plethora of studies have investigated clinical, pathological and mechanistic aspects of the disease. Loss of function is supported by reduced levels of C9orf72 in patient brain and functional work, revealing a role of the C9orf72 protein in endocytic and autophagic pathways and motor function. Gain of function is supported by the presence in patient brain of both repeat RNA and protein aggregates. Repeat RNA aggregates termed RNA foci, a hallmark of noncoding repeat expansion diseases, have been shown to sequester proteins involved in RNA splicing, editing, nuclear export and nucleolar function. Repeat-associated non-ATG dependent translation gives rise to toxic dipeptide repeat proteins that form inclusions in patient tissue. Antisense oligonucleotides targeting C9orf72 have shown promise for combating gain-of-function toxicity.SummaryRapid progress is being made towards understanding this common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Overall, the weight of data currently sits in favour of gain of function as the most important disease mechanism, which has important implications for the development of effective and targeted therapies.

Antisense Proline-Arginine RAN Dipeptides Linked to C9ORF72-ALS/FTD Form Toxic Nuclear Aggregates that Initiate In Vitro and In Vivo Neuronal Death

“…astrocytes and immortalized cell lines) were incubated with the synthetic peptides (Kwon et al, 2014). Toxicity of these arginine-rich peptides was also shown in vivo , in Drosophila models (Mizielinska and Isaacs, 2014). Another study showed, instead, that a different RAN translated species, poly-GA, caused toxicity measured by increased release of LDH, caspase-3 activation and endoplasmic reticulum stress when expressed in cultured cells and primary neurons (Zhang et al, 2014).…”

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

“…The pathogenic elements of C9ORF72 that involve both RNA and protein toxicity interact downstream with a large number of proteins, enzymes, and messengers, many of which have not yet been identified [79].…”

A genetic association study of two genes linked to neurodegeneration in a Sardinian multiple sclerosis population: The TARDBP Ala382Thr mutation and C9orf72 expansion

“…The biological role of the proteins codified by the gene analyzed in the present study is complex; firstly, their functions in cellular processes seem to be related to the gene expression regulation, including RNA splicing and transport [11,21]. The expansion of C9orf72 gene induce the formation of repeat RNA aggregates that are shown to sequester proteins involved in RNA splicing, editing, nuclear export and nucleolar function [22]. The overexpression of TDP-43 is shown to induce the activation of a transcription factor nuclear, NF-κB that is the master regulator of inflammation via the expression of several genes.…”

“…Its function in cellular processes involves the regulation of membrane trafficking and gene expression [21]. The expansion of C9orf72 gene induces the formation of repeat RNA aggregates that are shown to sequester proteins involved in RNA splicing, editing, nuclear export and nucleolar function [22]. The mechanism by which the expanded GGGGCC repeat could induce neurodegeneration is considered to be mediated by three mechanisms independent but not mutually exclusive: the mt C9orf72 toxicity haploinsufficiency, the generation of toxic RNA foci and peptide accumulation in neurons [23,24].…”