Elevated Peripheral Myelin Protein 22, Reduced Mitotic Potential, and Proteasome Impairment in Dermal Fibroblasts from Charcot-Marie-Tooth Disease Type 1A Patients
Open accessAbstract
A common form of hereditary autosomal dominant demyelinating neuropathy known as Charcot-Marie-Tooth disease type 1A (CMT1A) is linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Although studies from animal models have led to better understanding of the pathobiology of these neuropathies, there continues to be a gap in the translation of findings from rodents to humans. Because PMP22 was originally identified in fibroblasts as growth arrest specific gene 3 (gas3) and is expressed broadly in the body, it was tested whether skin cells from neuropathic patients would display the cellular pathology observed in Schwann cells from rodent models. Dermal fibroblasts from two CMT1A pedigrees with confirmed PMP22 gene duplication were studied. Samples from age-matched non-neuropathic individuals were used as controls. CMT1A patient-derived cultures contain approximately 1.5-fold elevated levels of PMP22 mRNA, exhibit reduced mitotic potential, and display intracellular protein aggregates as compared to cells from unaffected individuals. The presence of cytosolic PMP22 coincides with a decrease in proteasome activity and an increase in autophagy-lysosomal proteins, including LC3-II and LAMP1. These results indicate that the abnormalities in the subcellular processing of excess PMP22 elicit a detectable response in human CMT1A fibroblasts, a phenotype that resembles Schwann cells from neuropathic mice. These findings support the use of human CMT1A fibroblasts as a platform for therapy testing.
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Higher JUN/c-Jun in CMT1A may be part of a compensatory, neuroprotective response to the pathogenic effects of the PMP22 duplication.
“which may be part of a compensatory, neuroprotective response to the pathogenic effects of the PMP22 duplication [467–469].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [469]
In CMT1A, elevated Schwann cell autophagy is associated with higher levels of JUN/c-Jun.
“and associated with higher levels of JUN/c-Jun,”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [469]
In Charcot-Marie-Tooth type 1A caused by duplication of PMP22, Schwann cell autophagy is aberrantly elevated.
“in Charcot-Marie-Tooth (CMT) type 1A caused by duplication of PMP22 (peripheral myelin protein 22), Schwann cell autophagy is aberrantly elevated”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [469]
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Autophagy and ALS: mechanistic insights and therapeutic implications
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- Authors
- Lee, S., Bazick, H., Chittoor-Vinod, V., Al Salihi, M. O., Xia, G., & Notterpek, L.
- Affiliations
- University of Florida (US)
- University of Florida Health (US)
- Corresponding author
- Notterpek, Lucia
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 188
- Issue
- 3
- Pages
- 728-738
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC5842032
- OpenAlex
- W2773809639
- Cited by
- 41
- References
- 51
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 6 · 2021: 10 · 2020: 7 · 2019: 4 · 2018: 2
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- NIH (NS041012)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
- Keywords
- Charcot-Marie-Tooth disease type 1A, peripheral myelin protein 22, PMP22 gene duplication, dermal fibroblasts, demyelinating neuropathy, proteasome impairment, protein aggregates, autophagy-lysosome pathway, LC3-II, LAMP1, Schwann cells
- MeSH terms
- Adolescent, Adult, Charcot-Marie-Tooth Disease, Fibroblasts, Humans, Middle Aged, Myelin Proteins, Skin, Gene Duplication, Proteasome Endopeptidase Complex, Cell Proliferation, Young Adult
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