title: A53T human α-synuclein overexpression in transgenic mice induces pervasive mitochondria macroautophagy defects preceding dopamine neuron degeneration.
abstract: In vitro evidence suggests that the inefficient removal of damaged mitochondria by macroautophagy contributes to Parkinson's disease (PD). Using a tissue-specific gene amplification strategy, we generated a transgenic mouse line with human α-synuclein A53T overexpression specifically in dopamine (DA) neurons. Transgenic mice showed profound early-onset mitochondria abnormalities, characterized by macroautophagy marker-positive cytoplasmic inclusions containing mainly mitochondrial remnants, which preceded the degeneration of DA neurons. Genetic deletion of either parkin or PINK1 in these transgenic mice significantly worsened mitochondrial pathologies, including drastically enlarged inclusions and loss of total mitochondria contents. These data suggest that mitochondria are the main targets of α-synuclein and their defective autophagic clearance plays a significant role during pathogenesis. Moreover, endogenous PINK1 or parkin is indispensable for the proper autophagic removal of damaged mitochondria. Our data for the first time establish an essential link between mitochondria macroautophagy impairments and DA neuron degeneration in an in vivo model based on known PD genetics. The model, its well-defined pathologies, and the demonstration of a main pathogenesis pathway in the present study have set the stage and direction of emphasis for future studies.
authors.affiliation: Department of Neurobiology, University of Chicago, Chicago, Illinois 60637 lichen@bsd.uchicago.edu xzhuang@bsd.uchicago.edu.
authors.forename: Linan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, University of Chicago, Chicago, Illinois 60637.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Department of Neurobiology, University of Chicago, Chicago, Illinois 60637.
authors.forename: Susie
authors.identifier: http://orcid.org/0000-0001-9960-2404
authors.initials: S
authors.lastname: Turkson
authors.affiliation: Department of Neurobiology, University of Chicago, Chicago, Illinois 60637 lichen@bsd.uchicago.edu xzhuang@bsd.uchicago.edu.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002452:Cell Count; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
keywords: PINK1; alpha-synuclein; mitophagy; parkin; positive feedback; transgenic model