RT Journal Article
T1 C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease
A1 Goodier, John L.
A1 Soares, Alisha O.
A1 Pereira, Gavin C.
A1 DeVine, Lauren R.
A1 Sanchez, Laura
A1 Cole, Robert N.
A1 García-Pérez, Jose Luis
K1 Amyotrophic lateral sclerosis
K1 Autophagy
K1 Biomarker
K1 Mass spectrometry
K1 Proteasome
K1 Stress granules
K1 Ubiquitin
K1 Esclerosis amiotrófica lateral
K1 Autofagia
K1 Biomarcadores
K1 Espectrometría de masas
K1 Complejo de la endopetidasa proteasomal
K1 Ubiquitina
K1 Proteína C9orf72
AB A pathogenic GGGCCC hexanucleotide expansion in the first intron/promoter region of the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (ALS). The C9orf72 gene product forms a complex with SMCR8 (Smith-Magenis Syndrome Chromosome Region, Candidate 8) and WDR41 (WD Repeat domain 41) proteins. Recent studies have indicated roles for the complex in autophagy regulation, vesicle trafficking, and immune response in transgenic mice, however a direct connection with ALS etiology remains unclear. With the aim of increasing understanding of the multi-functional C9orf72-SMCR8-WDR41 complex, we determined by mass spectrometry analysis the proteins that directly associate with SMCR8. SMCR8 protein binds many components of the ubiquitin-proteasome system, and we demonstrate its poly-ubiquitination without obvious degradation. Evidence is also presented for localization of endogenous SMCR8 protein to cytoplasmic stress granules. However, in several cell lines we failed to reproduce previous observations that C9orf72 protein enters these granules. SMCR8 protein associates with many products of genes associated with various Mendelian neurological disorders in addition to ALS, implicating SMCR8-containing complexes in a range of neuropathologies. We reinforce previous observations that SMCR8 and C9orf72 protein levels are positively linked, and now show in vivo that SMCR8 protein levels are greatly reduced in brain tissues of C9orf72 gene expansion carrier individuals. While further study is required, these data suggest that SMCR8 protein level might prove a useful biomarker for the C9orf72 expansion in ALS.
PB BioMed Central, Springer Nature
YR 2020
FD 2020-07-16
LK http://hdl.handle.net/10668/3677
UL http://hdl.handle.net/10668/3677
LA en
NO Goodier JL, Soares AO, Pereira GC, DeVine LR, Sanchez L, Cole RN, et al. C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease. Acta Neuropathol Commun. 2020 Jul 16;8(1):110
DS RISalud
RD Apr 10, 2025