Premium
Loss of C9 ORF 72 impairs autophagy and synergizes with polyQ Ataxin‐2 to induce motor neuron dysfunction and cell death
Author(s) -
Sellier Chantal,
Campanari MariaLetizia,
Julie Corbier Camille,
Gaucherot Angeline,
KolbCheynel Isabelle,
OuladAbdelghani Mustapha,
Ruffenach Frank,
Page Adeline,
Ciura Sorana,
Kabashi Edor,
CharletBerguerand Nicolas
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201593350
Subject(s) - biology , motor neuron , autophagy , programmed cell death , microbiology and biotechnology , neuron , cell , apoptosis , neuroscience , biochemistry , spinal cord
An intronic expansion of GGGGCC repeats within the C9 ORF 72 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 C9 ORF 72 forms a complex with the WDR 41 and SMCR 8 proteins to act as a GDP / GTP exchange factor for RAB 8a and RAB 39b 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 . SMCR 8 is phosphorylated by TBK 1 and depletion of TBK 1 can be rescued by phosphomimetic mutants of SMCR 8 or by constitutively active RAB 39b, suggesting that TBK 1, SMCR 8, C9 ORF 72, and RAB 39b belong to a common pathway regulating autophagy. While depletion of C9 ORF 72 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 C9 ORF 72 is not deleterious by itself but synergizes with Ataxin‐2 toxicity, suggesting a double‐hit pathological mechanism in ALS ‐ FTD .