Cited by 414Amyotrophic Lateral Sclerosis ResearchGenetic Neurodegenerative DiseasesHereditary Neurological Disorders

Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin‐2 to induce motor neuron dysfunction and cell death

Open access
Sellier, Chantal, Campanari, Maria‐Letizia, Julie Corbier, Camille, Gaucherot, Angeline, Kolb‐Cheynel, Isabelle, Oulad‐Abdelghani, Mustapha, Ruffenach, Frank, Page, Adeline +3 more·2016·The EMBO Journal

Abstract

An intronic expansion of GGGGCC repeats within the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Ataxin-2 with intermediate length of polyglutamine expansions (Ataxin-2 Q30x) is a genetic modifier of the disease. Here, we found that C9ORF72 forms a complex with the WDR41 and SMCR8 proteins to act as a GDP/GTP exchange factor for RAB8a and RAB39b and to thereby control autophagic flux. Depletion of C9orf72 in neurons partly impairs autophagy and leads to accumulation of aggregates of TDP-43 and P62 proteins, which are histopathological hallmarks of ALS-FTD SMCR8 is phosphorylated by TBK1 and depletion of TBK1 can be rescued by phosphomimetic mutants of SMCR8 or by constitutively active RAB39b, suggesting that TBK1, SMCR8, C9ORF72, and RAB39b belong to a common pathway regulating autophagy. While depletion of C9ORF72 only has a partial deleterious effect on neuron survival, it synergizes with Ataxin-2 Q30x toxicity to induce motor neuron dysfunction and neuronal cell death. These results indicate that partial loss of function of C9ORF72 is not deleterious by itself but synergizes with Ataxin-2 toxicity, suggesting a double-hit pathological mechanism in ALS-FTD.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.15252/embj.201593350

Cites

122 of 122 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The C9orf72-SMCR8-WDR41 complex acts as a guanine nucleotide exchange factor for RAB8A and RAB39B, regulating vesicle trafficking and autophagic flux.

    “Separately, the C9orf72-SMCR8-WDR41 complex acts as a guanine nucleotide exchange factor for RAB8A and RAB39B, regulating vesicle trafficking and autophagic flux [148].”
  • C9orf72 forms a complex with SMCR8 and WDR41, which targets the complex to lysosomes and interacts with RB1CC1-ULK1-ATG13-ATG101 to regulate autophagosome formation.

    “C9orf72 also forms a complex with SMCR8, a guanine nucleotide exchange factor, and WDR41, a WD40 protein essential for targeting the C9orf72-SMCR8-WDR41 complex to lysosomes [146–150]. Here, this complex interacts with RB1CC1-ULK1-ATG13-ATG101, which together are involved in autophagosome formation [149].”
  • C9orf72 assists in the formation of nascent autophagosomes, consistent with impaired autophagy observed in murine cortical neurons and human iPSC-derived neurons upon C9orf72 knockdown.

    “Together, these findings suggest that C9orf72 assists in the formation of nascent autophagosomes, consistent with the finding of impaired autophagy in murine cortical neurons [148] and human iPSC-derived neurons [154] upon C9orf72 knockdown.”
  • TBK1 phosphorylates SMCR8, which forms a complex with C9orf72 and WDR41, thereby enhancing autophagy initiation.

    “TBK1 also phosphorylates SMCR8, which forms a complex with C9orf72 and WDR41, thereby enhancing autophagy initiation [148].”
  • In neurons, TBK1 knockdown enhances the accumulation of SQSTM1, which can be rescued by phosphomimetic SMCR8 mutations, suggesting that SMCR8 phosphorylation is crucial for TBK1's effects on autophagy.

    “In neurons, TBK1 knockdown enhances the accumulation of SQSTM1, which can be rescued by phosphomimetic SMCR8 mutations [148], suggesting that SMCR8 phosphorylation is crucial for TBK1’s effects on autophagy.”

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Dunlop EA, Seifan S, Claessens T, Behrends C, Kamps MA, Rozycka E, Kemp AJ, Nookala RK, Blenis J, Coull BJ, Murray JT, van Steensel MA, Wilkinson S, ª 2016 The Authors The EMBO Journal Vol 35 | No 12 | 2016

Cited by

Sorted by citations

Authors
Sellier, C., Campanari, M., Julie Corbier, C., Gaucherot, A., Kolb‐Cheynel, I., Oulad‐Abdelghani, M., Ruffenach, F., Page, A., Ciura, S., Kabashi, E., & Charlet‐Berguerand, N.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Sellier, Chantal
  • Charlet‐Berguerand, Nicolas
Venue
The EMBO Journal
Published
2016-04-21
Volume
35
Issue
12
Pages
1276-1297
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
OpenAlex
W2336528486
Cited by
414
References
122
Citations by year
2026: 19 · 2025: 22 · 2024: 33 · 2023: 30 · 2022: 31 · 2021: 72 · 2020: 53 · 2019: 45 · 2018: 47 · 2017: 42 · 2016: 20
FWCI
38.60
Type
journal article
Language
en
Open access
Locations
  • The EMBO Journal (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Fondation de France Thierry Latran (#57486)
  • ATIP‐Avenir INSERM
  • Robert Packard Foundation
  • E‐rare ERA‐NET program
  • AFM (#18605)
  • ARSLA
  • France‐Alzheimer Association (C9orfish)
  • Investissements d'avenir (ANR‐10‐IAIHU‐06)
  • Fondation Cognacq‐Jay
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
C9orf72, ATXN2, polyglutamine expansion, amyotrophic lateral sclerosis, frontotemporal dementia, autophagy, autophagic flux, Rab8a, RAB39B, SMCR8, TBK1, TDP-43 aggregation, motor neuron dysfunction, neuronal cell death, GGGGCC repeat expansion
MeSH terms
Ataxin-2, C9orf72 Protein, Amyotrophic Lateral Sclerosis, Autophagy, Humans, Motor Neurons, Peptides, Proteins, Cell Death, Frontotemporal Dementia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review