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Published on: June 18, 2018
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Mutant VPS35-D620N induces motor dysfunction and impairs DAT-mediated dopamine recycling pathway
Yi Huang1,2, Heng Huang1, Leping Zhou1
1Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases; National Key Clinical Department and Key Discipline of Neurology, Guangzhou 510080, China.
Human Molecular Genetics
|June 29, 2022
Summary
The VPS35-D620N mutation causes Parkinson disease by disrupting dopamine recycling and transporter function, leading to neuron loss and motor deficits. Reserpine treatment showed potential therapeutic benefits.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Late-onset familial Parkinson disease (PD) is linked to the D620N mutation in the vacuolar protein sorting protein 35 (VPS35) gene.
- The precise pathophysiological mechanisms of VPS35-D620N in PD pathogenesis remain largely unknown.
Purpose of the Study:
- To investigate the role of the PD-linked VPS35-D620N mutation in neuronal dysfunction and motor deficits.
- To elucidate the molecular mechanisms underlying VPS35-D620N-induced neurodegeneration, focusing on dopamine (DA) homeostasis and transport.
Main Methods:
- Generation of transgenic Caenorhabditis elegans (C. elegans) models overexpressing wild-type or mutant human VPS35-D620N in neurons.
- Assessment of motor function, dopaminergic neuron integrity, and dopamine recycling.
- Analysis of VPS35 protein interactions with dopamine transporter (DAT) and endosomal trafficking proteins (RAB5, RAB11, FAM21).
- Pharmacological evaluation of reserpine treatment on motor phenotypes.
Main Results:
- C. elegans expressing VPS35-D620N exhibited significant movement disorders and loss of dopaminergic neurons.
- VPS35-D620N disrupted the interaction with DAT and endosomal trafficking proteins, impairing DAT surface expression and DA recycling.
- Increased extracellular DA levels and subsequent dopaminergic neuron degeneration were observed.
- Reserpine treatment ameliorated the swimming-induced paralysis in VPS35-D620N worms.
Conclusions:
- The VPS35-D620N mutation impairs dopaminergic neuron function and survival by disrupting DAT trafficking and dopamine signaling pathways.
- These findings provide critical insights into PD mechanisms and suggest potential therapeutic strategies targeting DAT function for VPS35-related PD.
