C9orf72 isoforms in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

Xiao, Shangxi; MacNair, Laura; McLean, Jesse R.; McGoldrick, Phillip; McKeever, Paul M.; Soleimani, Serena; Keith, Julia; Zinman, Lorne; Rogaeva, Ekaterina; Robertson, Janice

doi:10.1016/j.brainres.2016.04.062

Cited by 41 publications

(59 citation statements)

References 67 publications

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“…The first study examining the normal cellular function of C9orf72 demonstrated that C9orf72 regulates endosomal trafficking and autophagy (Farg et al, 2014). More recent studies have confirmed these initial observations and also established that C9orf72 interacts with SMCR8 and WDR41 to form a complex that regulates the autophagy-lysosome pathway (Sellier et al, 2016; Sullivan et al, 2016; Xiao et al, 2016). Similarly, depletion of C9orf72 in primary cortical neurons has been reported to impair autophagy, leading to accumulation of TDP-43 and p62 aggregates (Sellier et al, 2016).…”

Section: C9orf72mentioning

confidence: 73%

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

Shahheydari

Ragagnin

Walker

et al. 2017

Front. Mol. Neurosci.

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Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials.

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Section: C9orf72mentioning

confidence: 73%

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

Shahheydari

Ragagnin

Walker

et al. 2017

Front. Mol. Neurosci.

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“…The three alternatively spliced C9ORF72 transcripts encode two C9ORF72 protein isoforms, a 222 amino acids (AA) protein isoform called C9-short (C9-S) and a 481AA protein isoform called C9-long (C9-L). The two protein isoforms have been shown by immunofluorescence to have distinct cellular localization with the C9-S lozalizing to the nuclear membrane and C9-L to the cytoplasm (Xiao et al, 2016). This observation suggests that the two isoforms have a different function, while the precise function of the protein has not been clearly determined.…”

Section: Introductionmentioning

confidence: 99%

New Antibody-Free Mass Spectrometry-Based Quantification Reveals That C9ORF72 Long Protein Isoform Is Reduced in the Frontal Cortex of Hexanucleotide-Repeat Expansion Carriers

et al. 2018

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Frontotemporal dementia (FTD) is a fatal neurodegenerative disease characterized by behavioral and language disorders. The main genetic cause of FTD is an intronic hexanucleotide repeat expansion (G4C2)n in the C9ORF72 gene. A loss of function of the C9ORF72 protein associated with the allele-specific reduction of C9ORF72 expression is postulated to contribute to the disease pathogenesis. To better understand the contribution of the loss of function to the disease mechanism, we need to determine precisely the level of reduction in C9ORF72 long and short isoforms in brain tissue from patients with C9ORF72 mutations. In this study, we developed a sensitive and robust mass spectrometry (MS) method for quantifying C9ORF72 isoform levels in human brain tissue without requiring antibody or affinity reagent. An optimized workflow based on surfactant-aided protein extraction and pellet digestion was established for optimal recovery of the two isoforms in brain samples. Signature peptides, common or specific to the isoforms, were targeted in brain extracts by multiplex MS through the parallel reaction monitoring mode on a Quadrupole–Orbitrap high resolution mass spectrometer. The assay was successfully validated and subsequently applied to frontal cortex brain samples from a cohort of FTD patients with C9ORF72 mutations and neurologically normal controls without mutations. We showed that the C9ORF72 short isoform in the frontal cortices is below detection threshold in all tested individuals and the C9ORF72 long isoform is significantly decreased in C9ORF72 mutation carriers.

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“…There are three C9ORF72 (C9) transcripts in humans: variant 1 (exons 2-5) encoding a 222-aa isoform defined as C9 short (C9-S) and variants 2 and 3 (exons 2-11) encoding a 481-aa isoform defined as C9 long (C9-L) [27]. The HREs are located in the promoter region of variant 2 and the first intron of variants 1 and 3.…”

Section: Introductionmentioning

confidence: 99%

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

et al. 2016

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The identification of the hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in the non-coding region of the C9ORF72 gene as the most frequent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has opened the path for advances in the knowledge and treatment of these disorders, which remain incurable. Recent evidence suggests that HRE RNA can cause gain-of-function neurotoxicity, but haploinsufficiency has also been hypothesized. In this review, we describe the recent developments in therapeutic targeting of the pathological expansion of C9ORF72 for ALS, FTD, and other neurodegenerative disorders. Three approaches are prominent: (1) an antisense oligonucleotides/RNA interference strategy; (2) using small compounds to counteract the toxic effects directly exerted by RNA derived from the repeat transcription (foci), by the translation of dipeptide repeat proteins (DPRs) from the repeated sequence, or by the sequestration of RNA-binding proteins from the C9ORF72 expansion; and (3) gene therapy, not only for silencing the toxic RNA/protein, but also for rescuing haploinsufficiency caused by the reduced transcription of the C9ORF72 coding sequence or by the diminished availability of RNA-binding proteins that are sequestered by RNA foci. Finally, with the perspective of clinical therapy, we Maria Sara Cipolat Mis and Simona Brajkovic contributed equally to this work.

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C9orf72 isoforms in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

Cited by 41 publications

References 67 publications

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

New Antibody-Free Mass Spectrometry-Based Quantification Reveals That C9ORF72 Long Protein Isoform Is Reduced in the Frontal Cortex of Hexanucleotide-Repeat Expansion Carriers

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

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