ArticleThe EMBO journal2016
Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death.
Article in The EMBO journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 273 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
273 citing papers in PubMed, 2 syntheses or guidelines pooled it, 396 citations in OpenAlex.
- Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD - a Systematic Review and Meta-Analysis.Cerebellum (London, England) · 2022Pooled it
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Roles of autophagy in brain homeostasis and disease.Nature neuroscience · 2026Review
- The Prospective Regulatory Functions of lncRNAs and Their ceRNA Networks in the Development of Motor Neurons and Associated Diseases.Biomolecules · 2026Review
- The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.The EMBO journal · 2026Article
- Multi-regional transcriptomic profiling reveals divergent molecular mechanisms in ALS-related neurodegeneration.PLoS genetics · 2026Article
- CYP46A1 activation by low-dose efavirenz uncovers the link between brain cholesterol metabolism, energetics, and vasculature.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2026Article
- Review
- Review
- Genetic epidemiology of C9orf72 repeat expansion associated amyotrophic lateral sclerosis in Hungary.Molecular medicine (Cambridge, Mass.) · 2026Article
- Article
- Review
- Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage.Molecular psychiatry · 2026Article
- Antisense Dipeptide Repeat Proteins Drive Widescale Purine Metabolism Aberration inInternational journal of molecular sciences · 2026Article
- Article
- C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.Frontiers in cellular neuroscience · 2026Article
- Genomic Organization, Evolutionary Conservation and Expression ofBiomedicines · 2025Article
- Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks.Cell reports · 2025Article
- Review
213 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.