Parkin-dependant degradation of caveolin-1 regulates lipid rafts-dependent endocytosis
Cha, Seon-Heui; Choi, Yuree; Kang, Seo-Jun; Park, Sang Myun
Department of Pharmacology, Ajou University School of Medicine; Chronic Inflammatory Disease Research Center, Ajou Research Institute for Innovative Medicine
Parkinson’s disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons resulting in motor dysfunctions. While most PD is sporadic in nature, a significant subset can be linked to either dominant or recessive germ line mutations. PARK2, encoding an E3 ubiquitin ligase, parkin, is the most frequently mutated gene in heredity PD. However, the molecular mechanism of parkin-deficiency-induced PD have not been clearly demonstrated, so great efforts have been made to elucidate the physiological target of parkin. It has recently been proposed that PD-associated gene products such as DJ-1, PINK1, α-synuclein, and LRRK2 as well as parkin reported to associate with lipid rafts, suggesting that the dysfunctions of them in lipid rafts may be a causal factor of PD. We examined, therefore, the relationship between lipid raft-related proteins and parkin. We identified caveolin-1 (cav-1), which is one of major constituents of lipid rafts on the plasma membrane, as a substrate of parkin. The loss of parkin function was found to disrupt the ubiquitination and degradation of cav-1, resulting in elevating cav-1 protein level in cells. Moreover, lipid rafts-dependent endocytosis was increased in parkin deficiency cells, suggesting that the dysregulation of lipid rafts dependent endocytosis by parkin deficiency would be a casual factor of PD.
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