ArticleJournal of cell science2011
Mutations associated with Charcot-Marie-Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome-autophagy pathways.
Article in Journal of cell science, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 71 citations in OpenAlex.
- Peripheral Myelin Protein-22 and Its Prominence in Charcot-Marie-Tooth Disease.Chemical reviews · 2026Review
- Schwann cell deletion ofmicroPublication biology · 2025Article
- Cytoprotective Role of Autophagy in CDIP1 Expression-Induced Apoptosis in MCF-7 Breast Cancer Cells.International journal of molecular sciences · 2024Article
- LITAF protects against pore-forming protein-induced cell death by promoting membrane repair.Science immunology · 2024Article
- Prenatal Chromosomal Microarray Analysis: Does Increased Resolution Equal Increased Yield?Genes · 2023Article
- Disruption of Endosomal Sorting in Schwann Cells Leads to Defective Myelination and Endosomal Abnormalities Observed in Charcot-Marie-Tooth Disease.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Apolipoprotein E4 Effects a Distinct Transcriptomic Profile and Dendritic Arbor Characteristics in Hippocampal Neurons CulturedFrontiers in aging neuroscience · 2022Article
- Wrestling and Wrapping: A Perspective on SUMO Proteins in Schwann Cells.Biomolecules · 2021Review
- Held Up in Traffic-Defects in the Trafficking Machinery in Charcot-Marie-Tooth Disease.Frontiers in molecular neuroscience · 2021Review
- A dysfunctional endolysosomal pathway common to two sub-types of demyelinating Charcot-Marie-Tooth disease.Acta neuropathologica communications · 2020Article
- Sequential CRISPR-Based Screens Identify LITAF and CDIP1 as the Bacillus cereus Hemolysin BL Toxin Host Receptors.Cell host & microbe · 2020Article
- The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement.International journal of molecular sciences · 2020Review
- Novel EGR2 variant that associates with Charcot-Marie-Tooth disease when combined with lipopolysaccharide-induced TNF-α factor T49M polymorphism.Neurology. Genetics · 2020Article
- Whole exome sequencing establishes diagnosis of Charcot-Marie-Tooth 4J, 1C, and X1 subtypes.Molecular genetics & genomic medicine · 2020Article
- Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis.Chemical reviews · 2019Article
- TDP-43 cytoplasmic inclusion formation is disrupted inBrain communications · 2019Article
- Hypertonia-linked protein Trak1 functions with mitofusins to promote mitochondrial tethering and fusion.Protein & cell · 2018Article
- Decreased ceramide underlies mitochondrial dysfunction in Charcot-Marie-Tooth 2F.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2018Article
- Article
- Charcot-Marie-Tooth disease type 1C: Clinical and electrophysiological findings for the c.334G>a (p.Gly112Ser) Litaf/Simple mutation.Muscle & nerve · 2017Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Mutations in SIMPLE cause an autosomal dominant, demyelinating form of peripheral neuropathy termed Charcot-Marie-Tooth disease type 1C (CMT1C), but the pathogenic mechanisms of these mutations remain unknown. Here, we report that SIMPLE is an early endosomal membrane protein that is highly expressed in the peripheral nerves and Schwann cells. Our analysis has identified a transmembrane domain (TMD) embedded within the cysteine-rich (C-rich) region that anchors SIMPLE to the membrane, and suggests that SIMPLE is a post-translationally inserted, C-tail-anchored membrane protein. We found that CMT1C-linked pathogenic mutations are clustered within or around the TMD of SIMPLE and that these mutations cause mislocalization of SIMPLE from the early endosome membrane to the cytosol. The CMT1C-associated SIMPLE mutant proteins are unstable and prone to aggregation, and they are selectively degraded by both the proteasome and aggresome-autophagy pathways. Our findings suggest that SIMPLE mutations cause CMT1C peripheral neuropathy by a combination of loss-of-function and toxic gain-of-function mechanisms, and highlight the importance of both the proteasome and autophagy pathways in the clearance of CMT1C-associated mutant SIMPLE proteins.
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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.