title: VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function.
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.
authors: Department of Neuroscience & Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30912, USA.
authors: Fu-Lei
authors: FL
authors: Tang
authors: Department of Neuroscience & Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Department of Ophthalmology and Institute of Surgery Research, Daping Hospital, Third Military Medical University, Shapingba, Chong-Qing 400042, China.
authors: Wei
authors: W
authors: Liu
authors: Institute of Nervous System Diseases, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors: Jin-Xia
authors: JX
authors: Hu
authors: Department of Neuroscience & Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors: Joanna Ruth
authors: JR
authors: Erion
authors: Department of Ophthalmology and Institute of Surgery Research, Daping Hospital, Third Military Medical University, Shapingba, Chong-Qing 400042, China.
authors: Jian
authors: J
authors: Ye
authors: Department of Neuroscience & Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors: Lin
authors: L
authors: Mei
authors: Department of Neuroscience & Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30912, USA. Electronic address: wxiong@gru.edu.
authors: Wen-Cheng
authors: WC
authors: Xiong
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D033921:Vesicular Transport Proteins; C101274:Vps35 protein, mouse; D051844:alpha-Synuclein; C000608240:MUL1 protein, mouse; D044767:Ubiquitin-Protein Ligases