Parkin, a critical gene of Parkinson's disease, is involved in the development of numerous cancers. However, the effect of parkin deficiency on melanoma growth and metastasis has not been reported. We showed that the tumor size and number of surface lung metastases, and expression of tumor growth and metastasis marker proteins were significantly lower in parkin-KO mice than those observed in non-transgenic controls. In an in vitro study, we also showed that parkin siRNA inhibited cell growth and migration of B16F10 and SK-Mel-28 cells. Parkin-specific ubiquitination of mitofusin-2 (MFN2) was decreased in tumors and metastasized lung tissues of parkin-KO mice. Moreover, we showed that parkin directly binds and ubiquitinates MFN2. Knockdown of MFN2 decreased the expression of Bax and apoptotic cell death, but increased that of Bcl2 and apoptotic cancer cell death. However, these effects were reversed by knockdown of parkin. Conversely, inhibitory effects on melanoma growth and migration of parkin siRNA were reversed by MFN2 siRNA. These data indicate that melanoma development was inhibited in parkin-KO mice through maintaining of MFN2 level by inhibition of ubiquitinating ability of parkin.
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Deficiency of parkin causes neurodegeneration and accumulation of pathological α-synuclein in monkey models.
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Article Synopsis
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- The study highlights that phosphorylated parkin plays a vital role in protecting against neurodegeneration and reducing toxic α-synuclein levels, indicating that targeting parkin phosphorylation could be a promising therapeutic strategy for PD.
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Department of Pharmacology, Ajou University School of Medicine, Suwon, South Korea; Center for Convergence Research of Neurological Disorders, Ajou University School of Medicine, Suwon, South Korea; Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, South Korea. Electronic address:
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Eur J Neurosci
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Department of Animal Physiology, Ruhr University Bochum, Bochum, Germany.
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NPJ Parkinsons Dis
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School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore.
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View Article and Find Full Text PDFPARIS farnesylation prevents neurodegeneration in models of Parkinson's disease.
Sci Transl Med
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Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea.
Accumulation of the parkin-interacting substrate (PARIS; ), due to inactivation of parkin, contributes to Parkinson's disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; ) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the promoter.
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