Department of Neurology, Yale University, New Haven, CT, USA; Department of Neuroscience, Yale University, New Haven, CT, USA
Mahalakshmi Somayaji
Department of Psychiatry, Columbia University, New York, NY, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
Nigel Wade
Department of Neurology, Yale University, New Haven, CT, USA; Department of Neuroscience, Yale University, New Haven, CT, USA
Betül Yücel
Department of Neurology, Yale University, New Haven, CT, USA; Department of Neuroscience, Yale University, New Haven, CT, USA
Helen Zhao
Department of Neurology, Yale University, New Haven, CT, USA
N. Shashaank
Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA; Department of Computer Science, Columbia University, New York, NY, USA; New York Genome Center, New York, NY, USA
Joseph Ribaudo
Department of Neurology, Yale University, New Haven, CT, USA
Jyoti Gupta
Department of Neuroscience, Yale University, New Haven, CT, USA
TuKiet T. Lam
Keck MS and Proteomics Resource, Departments of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Dalibor Sames
Department of Chemistry and NeuroTechnology Center, Columbia University, New York, NY, USA
Lois E. Greene
Laboratory of Cell Biology, NHLBI, National Institutes of Health, Bethesda, MD, USA
David L. Sulzer
Department of Psychiatry, Columbia University, New York, NY, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA; Departments of Neurology and Pharmacology, Columbia University, New York, NY, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
Sreeganga S. Chandra
Department of Neurology, Yale University, New Haven, CT, USA; Department of Neuroscience, Yale University, New Haven, CT, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA; Corresponding author
Summary: Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson’s disease (PD). Here, we utilized auxilin knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. Auxilin KO mice display cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Significantly, treatment with L-DOPA ameliorated motor deficits. Unbiased proteomic and neurochemical analyses of auxilin KO brains indicated dopamine dyshomeostasis. We validated these findings by demonstrating slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. Defective SV protein sorting and elevated synaptic autophagy also contribute to ineffective dopamine sequestration and compartmentalization, ultimately leading to neurodegeneration. This study provides insights into how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD.
