@misc{10481/63665,
year = {2020},
url = {http://hdl.handle.net/10481/63665},
abstract = {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.},
organization = {United States Department of Health & Human Services

National Institutes of Health (NIH) - USA

NIH National Institute of Neurological Disorders & Stroke (NINDS)

1R03NS087290-01},
organization = {United States Department of Health & Human Services

National Institutes of Health (NIH) - USA

NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)

R21HD083915-01A1},
organization = {ALS Therapy Alliance 	
2013-F-067},
organization = {European Research Council (ERC)

ERC-STG-2012-309433},
organization = {MINECO-FEDER 	
SAF2017-89745-R},
organization = {Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund (ISFF2)},
organization = {United States Department of Health & Human Services

National Institutes of Health (NIH) - USA

NIH National Center for Advancing Translational Sciences (NCATS)

UL1 TR003098},
publisher = {BMC},
keywords = {Amyotrophic lateral sclerosis},
keywords = {Autophagy},
keywords = {Biomarker},
keywords = {Mass spectrometry},
keywords = {Proteasome},
keywords = {Stress granules},
keywords = {Ubiquitin},
title = {C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease},
doi = {10.1186/s40478-020-00982-x},
author = {García Pérez, José Luis and Sánchez, Laura and Goodier, John L.},
}