Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of the corticospinal motor neurons, which ultimately leads to death. The repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) represents the most common genetic cause of ALS and it is also involved in the pathogenesis of other neurodegenerative disorders. To offer insights into C9ORF72-mediated pathogenesis, we quantitatively analyzed the proteome of patient-derived primary skin fibroblasts from ALS patients carrying the C9ORF72 mutation compared with ALS patients who tested negative for it. Differentially expressed proteins were identified, used to generate a protein-protein interaction network and subjected to a functional enrichment analysis to unveil altered molecular pathways. ALS patients were also compared with patients affected by frontotemporal dementia carrying the C9ORF72 repeat expansion. As a result, we demonstrated that the molecular pathways mainly altered in fibroblasts (e.g., protein homeostasis) mirror the alterations observed in C9ORF72-mutated neurons. Moreover, we highlighted novel molecular pathways (nuclear and mitochondrial transports, vesicle trafficking, mitochondrial bioenergetics, glucose metabolism, ER-phagosome crosstalk and Slit/Robo signaling pathway) which might be further investigated as C9ORF72-specific pathogenetic mechanisms. Data are available via ProteomeXchange with the identifier PXD023866.
Highlights
The GGGGCC hexanucleotide repeat expansion of chromosome 9 open reading frame72 (C9ORF72) gene is the most common genetic mutation in amyotrophic lateral sclerosis (ALS), where it accounts for approximately 40% and 6% of the familial and sporadic cases, respectively [1]
We showed the results of a proteomics analysis performed on primary skin fibroblast cell lines from Amyotrophic lateral sclerosis (ALS) patients with the aim of unveiling pathogenetic mechanisms related to the chromosome 9 open reading frame 72 (C9ORF72) repeat expansion
By using a proteomics approach coupled to a network-based systems biology analysis, we shed some light on the molecular mechanisms underlying C9ORF72-mediated pathogenesis
Summary
The GGGGCC hexanucleotide repeat expansion of chromosome 9 open reading frame72 (C9ORF72) gene is the most common genetic mutation in amyotrophic lateral sclerosis (ALS), where it accounts for approximately 40% and 6% of the familial and sporadic cases, respectively [1]. Two other pathogenetic mechanisms have been proposed: (i) toxicity due to the aggregation of dipeptide repeats produced by non-ATG-mediated RNA translation; and (ii) loss-of-function of the C9ORF72 protein by means of haploinsufficiency [6]. Proteostasis and neuronal processes are known to be impaired in C9ORF72-mediated pathogenesis, including lysosomal function, ubiquitin-proteasome system (UPS), unfolded protein response (UPR), axonal transport and immune function [12]. In other words, both loss- and gain-of-function mechanisms are implicated in C9ORF72-mediated pathogenesis. The gain-of-function ones support the formation of toxic aggregates (both RNA and proteins), whereas the loss-of-function mechanisms mainly impair vesicle trafficking and autophagy
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