ArticleHuman molecular genetics2019
Smcr8 deficiency disrupts axonal transport-dependent lysosomal function and promotes axonal swellings and gain of toxicity in C9ALS/FTD mouse models.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 13 papers, 1 of them a synthesis that pooled it.
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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.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 18 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
- Autophagy markers LC3 and p62 in aging lumbar motor neurons.Experimental gerontology · 2024Article
- Reversing lysosome-ribosome circuit dysregulation mitigates C9FTD/ALS neurodegeneration and behaviors.Human molecular genetics · 2023Article
- C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice.Frontiers in cellular neuroscience · 2023Article
- Article
- Small junction, big problems: Neuromuscular junction pathology in mouse models of amyotrophic lateral sclerosis (ALS).Journal of anatomy · 2022Review
- The progress inSmall GTPases · 2022Review
- C9orf72 ALS-FTD: recent evidence for dysregulation of the autophagy-lysosome pathway at multiple levels.Autophagy · 2021Review
- Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture.PLoS biology · 2021Article
- Proteostatic imbalance and protein spreading in amyotrophic lateral sclerosis.The EMBO journal · 2021Review
- KIF5A-dependent axonal transport deficiency disrupts autophagic flux in trimethyltin chloride-induced neurotoxicity.Autophagy · 2021Article
- Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion.Frontiers in cellular neuroscience · 2021Article
- C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease.Acta neuropathologica communications · 2020Article
Corrections and comments
- Erratum issued
Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
G4C2 repeat expansions in an intron of C9ORF72 cause the most common familial amyotrophic lateral sclerosis and frontotemporal dementia (collectively, C9ALS/FTD). Mechanisms and mediators of C9ALS/FTD pathogenesis remain poorly understood. C9orf72 and Smcr8 form a protein complex. Here, we show that expression of Smcr8, like C9orf72, is reduced in C9ALS/FTD mouse models and patient tissues. Since Smcr8 is highly conserved between human and mouse, we evaluated the effects of Smcr8 downregulation in mice. Smcr8 knockout (KO) mice exhibited motor behavior deficits, which resemble those of C9ALS/FTD mouse models, and displayed axonal swellings in their spinal cords and neuromuscular junctions. These deficits are caused by impaired autophagy-lysosomal functions due to disrupted axonal transport in mutant motor neurons. Consistent with its interaction with C9orf72 and their downregulation in patient tissues, Smcr8 deficiency exacerbated autophagy-lysosomal impairment in C9orf72 KO mice. The disease relevance of Smcr8 downregulation was reflected by exacerbated axonal swellings and gain of toxicity pathology arising from Smcr8 haploinsufficiency in a mouse model of C9ALS/FTD. Thus, our in vivo studies suggested that Smcr8 deficiency impairs axonal transport dependent autophagy-lysosomal function and exacerbates axonal degeneration and gain of toxicity in C9ALS/FTD mouse models.
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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.