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

Cell Rep. 2015 Sep 8;12(10):1631-43. doi: 10.1016/j.celrep.2015.08.001. Epub 2015 Aug 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Dopaminergic Neurons / physiology*
  • Membrane Potential, Mitochondrial
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / physiology
  • Mitochondrial Dynamics*
  • Mitochondrial Proteins / metabolism
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Protein Transport
  • Ubiquitin-Protein Ligases / metabolism
  • Vesicular Transport Proteins / genetics*
  • Vesicular Transport Proteins / metabolism
  • alpha-Synuclein / metabolism


  • Mitochondrial Proteins
  • Vesicular Transport Proteins
  • Vps35 protein, mouse
  • alpha-Synuclein
  • MUL1 protein, mouse
  • Ubiquitin-Protein Ligases