@article{ceeb92b929a14b3aa6848e1bcc423777,
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{\textquoteright}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",
author = "Mian Cao and Yumei Wu and Ghazaleh Ashrafi and McCartney, {Amber J.} and Heather Wheeler and Bushong, {Eric A.} and Daniela Boassa and Ellisman, {Mark H.} and Ryan, {Timothy A.} and {De Camilli}, Pietro",
note = "Funding Information: We thank Sreeganga Chandra, Shawn Ferguson, Nii Addy, and Yiying Cai for discussion; Frank Wilson, Louise Lucast, Lijuan Liu, Alvaro Duque, and Lucy Saidenberg for technical assistance; Sheng Ding, Tian Xu, and Sreeganga Chandra for sharing animal behavioral test instruments; Caroline Zeiss for mouse pathology service and discussion; and Caiying Guo (Janelia Research Campus mouse facility) for the generation of knockin mouse. This work was supported in part by grants from the NIH (NS36251 and DA18343 to P.D.C. and NS036942 to T.A.R.), the Michael J. Fox Foundation (11353 to P.D.C. and M.C.), NIH GM103412 (M.H.E.) for support of the National Center for Microscopy and Imaging Research, The Branfman Family Foundation (M.H.E. and D.B.), and by a postdoctoral fellowship from the Parkinson's Disease Foundation to M.C. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = feb,
day = "22",
doi = "10.1016/j.neuron.2017.01.019",
language = "English",
volume = "93",
pages = "882--896.e5",
journal = "Neuron",
issn = "0896-6273",
number = "4",
}