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

ABSTRACT: 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 dys-homeostasis. 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 advances our knowledge of how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Parkinson's Disease

SUBMITTER: TuKiet Lam

LAB HEAD: TuKiet Lam

PROVIDER: PXD040141 | Pride | 2023-02-16

REPOSITORIES: Pride

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Project description:Background: Molecular adaptations in the striatum mediated by dopamine (DA) denervation or Levodopa (L-dopa) treatment have been implicated with the motor deficits found in Parkinsonâ??s disease (PD). Alterations in glutamatergic neurotransmission and anti-oxidant mechanisms are reported to play important roles in mediating these changes. However, the mechanisms mediating the molecular adaptations in the striatum are not well understood. In recent years, microRNAs (miRNAs) have been recognized as potent post-transcriptional regulators of gene expression with fundamental roles in numerous biological processes. miRNAs are known to influence the development and maintenance of striatal neurons. Therefore, we sought to determine the genome-wide expression levels of miRNAs in PD striatal tissues. Methods: Using a digital gene expression platform to quantify miRNA levels, we compared the expression of 800 miRNAs in human postmortem putamen tissues from PD patients and controls. Results: We detected the expression of approximately 250 miRNAs in postmortem human putamen samples collected from patients with PD and healthy controls. There was an abundance of a subset of 17 miRNAs (10 up- and 7 down-regulated) differing substantially between PD and the control tissues. Conclusions: We identified deregulated miRNAs most likely associated with altered striatal functions found in PD. This approach may provide insight into pathogenesis and additional therapeutic targets for the development novel treatment strategies for the disease. Human postmortem putamen tissues from 12 patients with PD symptoms and 12 neurologically normal controls. Samples were obtained from the Human Brain and Spinal Fluid Resource Center, Los Angeles, CA through NIH NeuroBioBank, and stored at -80Â°C until RNA isolation. Total RNA was extracted using the miRVana RNA isolation kit, following the manufacturerâ??s instructions (Ambion). Using 225ng total RNA, miRNA levels were assayed by direct digital detection using Nanostring miRNA assay kits (Nanostring Technologies).

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

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