title: Parkinson Sac Domain Mutation in Synaptojanin 1 Impairs Clathrin Uncoating at Synapses and Triggers Dystrophic Changes in Dopaminergic Axons.
abstract: Synaptojanin 1 (SJ1) is a major presynaptic phosphatase that couples synaptic vesicle endocytosis to the dephosphorylation of PI(4,5)P2, a reaction needed for the shedding of endocytic factors from their membranes. While the role of SJ1's 5-phosphatase module in this process is well recognized, the contribution of its Sac phosphatase domain, whose preferred substrate is PI4P, remains unclear. Recently a homozygous mutation in its Sac domain was identified in early-onset parkinsonism patients. We show that mice carrying this mutation developed neurological manifestations similar to those of human patients. Synapses of these mice displayed endocytic defects and a striking accumulation of clathrin-coated intermediates, strongly implicating Sac domain's activity in endocytic protein dynamics. Mutant brains had elevated auxilin (PARK19) and parkin (PARK2) levels. Moreover, dystrophic axonal terminal changes were selectively observed in dopaminergic axons in the dorsal striatum. These results strengthen evidence for a link between synaptic endocytic dysfunction and Parkinson's disease.
authors.affiliation: Departments of Neuroscience and Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Kavli Institute for Neuroscience, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Mian
authors.initials: M
authors.lastname: Cao
authors.affiliation: Departments of Neuroscience and Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Kavli Institute for Neuroscience, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Ashrafi
authors.affiliation: Departments of Neuroscience and Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Kavli Institute for Neuroscience, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Amber J
authors.initials: AJ
authors.lastname: McCartney
authors.affiliation: Departments of Neuroscience and Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Kavli Institute for Neuroscience, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Wheeler
authors.affiliation: Center for Research in Biological Systems and the National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Bushong
authors.affiliation: Center for Research in Biological Systems and the National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Boassa
authors.affiliation: Center for Research in Biological Systems and the National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Ryan
authors.affiliation: Departments of Neuroscience and Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Kavli Institute for Neuroscience, School of Medicine, Yale University, New Haven, CT 06510, USA. Electronic address: pietro.decamilli@yale.edu.
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D002966:Clathrin / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D004705:Endocytosis / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D013569:Synapses / Q000378:metabolism*; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D002966:Clathrin; D004298:Dopamine; D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases
keywords: LRRK2; PARK19; PARK2; PARK20; PI(4,5)P2; Parkin; auxilin; neurodegeneration; nigrostriatal pathway; synaptic vesicle endocytosis; synaptojanin 1