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PMID: 28231468 Published · ppublish English Journal Article

Parkinson Sac Domain Mutation in Synaptojanin 1 Impairs Clathrin Uncoating at Synapses and Triggers Dystrophic Changes in Dopaminergic Axons.

Neuron ·Vol. 93 ·No. 4 ·2017-02-22 ·Pages 882-896.e5

Cao M, Wu Y, Ashrafi G, McCartney AJ, Wheeler H, Bushong EA, Boassa D, Ellisman MH, Ryan TA, De Camilli P

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.

Keywords
LRRK2 PARK19 PARK2 PARK20 PI(4 5)P2 Parkin auxilin neurodegeneration nigrostriatal pathway synaptic vesicle endocytosis synaptojanin 1
MeSH Terms
Animals Axons/metabolism Clathrin/metabolism Dopamine/metabolism Endocytosis/genetics,physiology Humans Mice, Transgenic Mutation/genetics Parkinson Disease/genetics,metabolism Parkinsonian Disorders/genetics,metabolism Phosphoric Monoester Hydrolases/genetics Synapses/metabolism
Chemicals
Clathrin Phosphoric Monoester Hydrolases phosphoinositide 5-phosphatase Dopamine
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Cao Mian
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.
Wu Yumei
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.
Ashrafi Ghazaleh
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA.
McCartney Amber J
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.
Wheeler Heather
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.
Bushong Eric A
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.
Boassa Daniela
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.
Ellisman Mark H
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.
Ryan Timothy A
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA.
De Camilli Pietro
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: [email protected].
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Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2017.01.019
Email
[email protected]
Published
2017-02-22
Pages
882-896.e5
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC5340420
Subset
IM
Grants
NINDS NIH HHS · R01 NS036942 · United States
NIGMS NIH HHS · P41 GM103412 · United States
NCATS NIH HHS · UL1 TR001863 · United States
NIDA NIH HHS · P30 DA018343 · United States
NINDS NIH HHS · R01 NS036251 · United States
NINDS NIH HHS · R37 NS036251 · United States
NINDS NIH HHS · R37 NS036942 · United States
Corrections
CommentIn
PMID: 28681957
External Links
PubMed source DOI: 10.1016/j.neuron.2017.01.019 PMC Full Text View journal details
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