title: Loss of parkin promotes lipid rafts-dependent endocytosis through accumulating caveolin-1: implications for Parkinson's disease.
abstract: BACKGROUND
  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 autosomal dominant or recessive mutations. PARK2, encoding the E3 ubiquitin ligase, parkin, is the most frequently mutated gene in autosomal recessive early onset PD. It has recently been reported that PD-associated gene products such as PINK1, α-synuclein, LRRK2, and DJ-1, as well as parkin associate with lipid rafts, suggesting that the dysfunction of these proteins in lipid rafts may be a causal factor of PD. Therefore here, we examined the relationship between lipid rafts-related proteins and parkin.
  
  
  RESULTS
  We identified caveolin-1 (cav-1), which is one of the major constituents of lipid rafts at the plasma membrane, as a substrate of parkin. Loss of parkin function was found to disrupt the ubiquitination and degradation of cav-1, resulting in elevated cav-1 protein level in cells. Moreover, the total cholesterol level and membrane fluidity was altered by parkin deficiency, causing dysregulation of lipid rafts-dependent endocytosis. Further, cell-to-cell transmission of α-synuclein was facilitated by parkin deficiency.
  
  
  CONCLUSIONS
  Our results demonstrate that alterations in lipid rafts by the loss of parkin via cav-1 may be a causal factor of PD, and cav-1 may be a novel therapeutic target for PD.
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon, 16499, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Seon-Heui
authors.initials: SH
authors.lastname: Cha
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon, 16499, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.|Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Yu Ree
authors.initials: YR
authors.lastname: Choi
authors.affiliation: Department of Chemistry, Ajou University, Suwon, Korea.
authors.forename: Cheol-Ho
authors.initials: CH
authors.lastname: Heo
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon, 16499, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.|Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Seo-Jun
authors.initials: SJ
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon, 16499, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.|Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Joe
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon, 16499, Korea.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.|Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Ilo
authors.initials: I
authors.lastname: Jou
authors.affiliation: Department of Chemistry, Ajou University, Suwon, Korea.
authors.forename: Hwan-Myung
authors.initials: HM
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon, 16499, Korea. sangmyun@ajou.ac.kr.|Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea. sangmyun@ajou.ac.kr.|Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Korea. sangmyun@ajou.ac.kr.
authors.forename: Sang Myun
authors.initials: SM
authors.lastname: Park
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000235:genetics* / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein