Abstract | OBJECTIVES:
Chloroquine (CQ) is an antimalarial drug with a growing number of applications as recently demonstrated in attempts to treat Covid-19. For decades, it has been well known that skeletal and cardiac muscle cells might display vulnerability against CQ exposure resulting in the clinical manifestation of a CQ-induced myopathy. In line with the known effect of CQ on inhibition of the lysosomal function and thus cellular protein clearance, the build-up of autophagic vacuoles along with protein aggregates is a histological hallmark of the disease. Given that protein targets of the perturbed proteostasis are still not fully discovered, we applied different proteomic and immunological-based studies to improve the current understanding of the biochemical nature of CQ- myopathy. METHODS: To gain a comprehensive understanding of the molecular pathogenesis of this acquired myopathy and to define proteins targets as well as pathophysiological processes beyond impaired proteolysis, utilising CQ-treated C2C12 cells and muscle biopsies derived from CQ- myopathy patients, we performed different proteomic approaches and Coherent Anti-Stokes Raman Scattering (CARS) microscopy, in addition to immunohistochemical studies. RESULTS: Our combined studies confirmed an impact of CQ-exposure on proper protein processing/folding and clearance, highlighted changes in the interactome of p62, a known aggregation marker and hereby identified the Rett syndrome protein MeCP2 as being affected. Moreover, our approach revealed-among others-a vulnerability of the extracellular matrix, cytoskeleton and lipid homeostasis. CONCLUSION: We demonstrated that CQ exposure (secondarily) impacts biological processes beyond lysosomal function and linked a variety of proteins with known roles in the manifestation of other neuromuscular diseases.
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Authors | Vietxuan Phan, Denisa Hathazi, Corinna Preuße, Artur Czech, Erik Freier, Gerta Shema, René P Zahedi, Andreas Roos |
Journal | Neuropathology and applied neurobiology
(Neuropathol Appl Neurobiol)
Vol. 49
Issue 1
Pg. e12877
(02 2023)
ISSN: 1365-2990 [Electronic] England |
PMID | 36633103
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2023 British Neuropathological Society. |
Chemical References |
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Topics |
- Humans
- Chloroquine
(pharmacology)
- Proteomics
- COVID-19
- COVID-19 Drug Treatment
- Proteins
- Muscular Diseases
- Muscle Cells
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