VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function

Fulei Tang, Wei Liu, Jin Xia Hu, Joanna Ruth Appel, Jian Ye, Lin Mei, Wencheng Xiong

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

Vacuolar protein sorting-35 (VPS35) is a retromer component for endosomal trafficking. Mutations of VPS35 have been linked to familial Parkinson's disease (PD). Here, we show that specific deletion of the VPS35 gene in dopamine (DA) neurons resulted in PD-like deficits, including loss of DA neurons and accumulation of α-synuclein. Intriguingly, mitochondria became fragmented and dysfunctional in VPS35-deficient DA neurons, phenotypes that could be restored by expressing VPS35 wild-type, but not PD-linked mutant. Concomitantly, VPS35 deficiency or mutation increased mitochondrial E3 ubiquitin ligase 1 (MUL1) and, thus, led to mitofusin 2 (MFN2) degradation and mitochondrial fragmentation. Suppression of MUL1 expression ameliorated MFN2 reduction and DA neuron loss but not α-synuclein accumulation. These results provide a cellular mechanism for VPS35 dysfunction in mitochondrial impairment and PD pathogenesis. Tang et al. find that VPS35 in mouse dopaminergic neurons is required for preventing dopaminergic neuronal loss. The function of VPS35 on dopamine neuronal survival is likely due to VPS35 promotion of MUL1 degradation, thus increasing MFN2 protein stability and mitochondrial fusion.

Original languageEnglish (US)
Pages (from-to)1631-1643
Number of pages13
JournalCell Reports
Volume12
Issue number10
DOIs
StatePublished - Sep 8 2015

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Mitochondrial Dynamics
Protein Transport
Sorting
Fusion reactions
Dopaminergic Neurons
Mutation
Neurons
Proteins
Ubiquitin-Protein Ligases
Dopamine
Synucleins
Parkinson Disease
Protein Stability
Degradation
Mitochondria
Phenotype
Genes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function. / Tang, Fulei; Liu, Wei; Hu, Jin Xia; Appel, Joanna Ruth; Ye, Jian; Mei, Lin; Xiong, Wencheng.

In: Cell Reports, Vol. 12, No. 10, 08.09.2015, p. 1631-1643.

Research output: Contribution to journalArticle

Tang, Fulei ; Liu, Wei ; Hu, Jin Xia ; Appel, Joanna Ruth ; Ye, Jian ; Mei, Lin ; Xiong, Wencheng. / VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function. In: Cell Reports. 2015 ; Vol. 12, No. 10. pp. 1631-1643.
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