title: VPS35 in Dopamine Neurons Is Required for Endosome-to-Golgi Retrieval of Lamp2a, a Receptor of Chaperone-Mediated Autophagy That Is Critical for α-Synuclein Degradation and Prevention of Pathogenesis of Parkinson's Disease.
abstract: Vacuolar protein sorting-35 (VPS35) is essential for endosome-to-Golgi retrieval of membrane proteins. Mutations in the VPS35 gene have been identified in patients with autosomal dominant PD. However, it remains poorly understood if and how VPS35 deficiency or mutation contributes to PD pathogenesis. Here we provide evidence that links VPS35 deficiency to PD-like neuropathology. VPS35 was expressed in mouse dopamine (DA) neurons in substantia nigra pars compacta (SNpc) and STR (striatum)--regions that are PD vulnerable. VPS35-deficient mice exhibited PD-relevant deficits including accumulation of α-synuclein in SNpc-DA neurons, loss of DA transmitter and DA neurons in SNpc and STR, and impairment of locomotor behavior. Further mechanical studies showed that VPS35-deficient DA neurons or DA neurons expressing PD-linked VPS35 mutant (D620N) had impaired endosome-to-Golgi retrieval of lysosome-associated membrane glycoprotein 2a (Lamp2a) and accelerated Lamp2a degradation. Expression of Lamp2a in VPS35-deficient DA neurons reduced α-synuclein, supporting the view for Lamp2a as a receptor of chaperone-mediated autophagy to be critical for α-synuclein degradation. These results suggest that VPS35 deficiency or mutation promotes PD pathogenesis and reveals a crucial pathway, VPS35-Lamp2a-α-synuclein, to prevent PD pathogenesis. Significance statement: VPS35 is a key component of the retromer complex that is essential for endosome-to-Golgi retrieval of membrane proteins. Mutations in the VPS35 gene have been identified in patients with PD. However, if and how VPS35 deficiency or mutation contributes to PD pathogenesis remains unclear. We demonstrated that VPS35 deficiency or mutation (D620N) in mice leads to α-synuclein accumulation and aggregation in the substantia nigra, accompanied with DA neurodegeneration. VPS35-deficient DA neurons exhibit impaired endosome-to-Golgi retrieval of Lamp2a, which may contribute to the reduced α-synuclein degradation through chaperone-mediated autophagy. These results suggest that VPS35 deficiency or mutation promotes PD pathogenesis, and reveals a crucial pathway, VPS35-Lamp2a-α-synuclein, to prevent PD pathogenesis.
authors.affiliation: Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, Charlie Norwood VA Medical Center, Augusta, Georgia 30912.
authors.forename: Fu-Lei
authors.initials: FL
authors.lastname: Tang
authors.affiliation: Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912.
authors.forename: Joanna R
authors.identifier: http://orcid.org/0000-0002-5625-5059
authors.initials: JR
authors.lastname: Erion
authors.affiliation: Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, Department of Neurology, Xiang-Ya Hospital, Central South University, Changsha, Hunan, P.R. China 410083, and.
authors.forename: Yun
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, Department of Ophthalmology and Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, P.R. China 400042.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912.
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Yin
authors.affiliation: Department of Ophthalmology and Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, P.R. China 400042.
authors.forename: Jian
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Neurology, Xiang-Ya Hospital, Central South University, Changsha, Hunan, P.R. China 410083, and.
authors.forename: Baisha
authors.initials: B
authors.lastname: Tang
authors.affiliation: Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, Charlie Norwood VA Medical Center, Augusta, Georgia 30912.
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.affiliation: Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, Charlie Norwood VA Medical Center, Augusta, Georgia 30912, wxiong@gru.edu.
authors.forename: Wen-Cheng
authors.identifier: http://orcid.org/0000-0001-9071-7598
authors.initials: WC
authors.lastname: Xiong
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D011992:Endosomes / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D016297:Mutagenesis, Site-Directed; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D052119:Lysosomal-Associated Membrane Protein 2; D033921:Vesicular Transport Proteins; C101274:Vps35 protein, mouse; D051844:alpha-Synuclein
keywords: LAMP2a; Parkinson's disease; VPS35; autophagy; α-synuclein