ArticleActa neuropathologica communications2020
C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease.
Article in Acta neuropathologica communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 19 citations in OpenAlex.
- Exploring dysregulated miRNAs in ALS: implications for disease pathogenesis and early diagnosis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Pooled it
- Microglial Dysfunction Induced by C9ORF72 Dipeptide Repeat Proteins: Biomarker and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Lysosomal homeostasis at the crossroads of neurodegeneration.The Journal of clinical investigation · 2026Review
- Artificial Intelligence-Assisted Comparative Analysis of the Overlapping Molecular Pathophysiology of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia.International journal of molecular sciences · 2024Article
- Genome-wide association and replication studies for handedness in a Korean community-based cohort.Brain and behavior · 2023Article
- ZCCHC3 is a stress granule zinc knuckle protein that strongly suppresses LINE-1 retrotransposition.PLoS genetics · 2023Article
- Molecular Chaperones' Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis.Cells · 2023Review
- Unraveling the impact of disrupted nucleocytoplasmic transport systems inFrontiers in cellular neuroscience · 2023Review
- Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis.Scientific reports · 2022Article
- Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture.PLoS biology · 2021Article
- The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors.Journal of neuropathology and experimental neurology · 2021Review
- Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting.Cells · 2020Article
- Article
- The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement.International journal of molecular sciences · 2020Review
- Emerging Roles of Tripartite Motif-Containing Family Proteins (TRIMs) in Eliminating Misfolded Proteins.Frontiers in cell and developmental biology · 2020Review
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
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.
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