Cell Reports (Mar 2023)

Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease

  • D.J. Vidyadhara,
  • Mahalakshmi Somayaji,
  • Nigel Wade,
  • Betül Yücel,
  • Helen Zhao,
  • N. Shashaank,
  • Joseph Ribaudo,
  • Jyoti Gupta,
  • TuKiet T. Lam,
  • Dalibor Sames,
  • Lois E. Greene,
  • David L. Sulzer,
  • Sreeganga S. Chandra

Journal volume & issue
Vol. 42, no. 3
p. 112231

Abstract

Read online

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.

Keywords