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

Fu Lei Tang, Joanna R. Erion, Yun Tian, Wei Liu, Dong Min Yin, Jian Ye, Baisha Tang, Lin Mei, Wen Cheng Xiong

Research output: Contribution to journalArticle

93 Citations (Scopus)

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 ofα-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- deficientDAneurons reducedα-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.

Original languageEnglish (US)
Pages (from-to)10613-10628
Number of pages16
JournalJournal of Neuroscience
Volume35
Issue number29
DOIs
StatePublished - Jul 22 2015

Fingerprint

Synucleins
Lysosome-Associated Membrane Glycoproteins
Endosomes
Dopaminergic Neurons
Autophagy
Protein Transport
Parkinson Disease
Mutation
Dopamine
Membrane Proteins

Keywords

  • Autophagy
  • LAMP2a
  • Parkinson’s disease
  • VPS35
  • α-synuclein

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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. / Tang, Fu Lei; Erion, Joanna R.; Tian, Yun; Liu, Wei; Yin, Dong Min; Ye, Jian; Tang, Baisha; Mei, Lin; Xiong, Wen Cheng.

In: Journal of Neuroscience, Vol. 35, No. 29, 22.07.2015, p. 10613-10628.

Research output: Contribution to journalArticle

@article{b119dc4208c045a09df0acdd8ec2d3a3,
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 ofα-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- deficientDAneurons reducedα-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.",
keywords = "Autophagy, LAMP2a, Parkinson’s disease, VPS35, α-synuclein",
author = "Tang, {Fu Lei} and Erion, {Joanna R.} and Yun Tian and Wei Liu and Yin, {Dong Min} and Jian Ye and Baisha Tang and Lin Mei and Xiong, {Wen Cheng}",
year = "2015",
month = "7",
day = "22",
doi = "10.1523/JNEUROSCI.0042-15.2015",
language = "English (US)",
volume = "35",
pages = "10613--10628",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "29",

}

TY - JOUR

T1 - 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

AU - Tang, Fu Lei

AU - Erion, Joanna R.

AU - Tian, Yun

AU - Liu, Wei

AU - Yin, Dong Min

AU - Ye, Jian

AU - Tang, Baisha

AU - Mei, Lin

AU - Xiong, Wen Cheng

PY - 2015/7/22

Y1 - 2015/7/22

N2 - 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 ofα-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- deficientDAneurons reducedα-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.

AB - 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 ofα-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- deficientDAneurons reducedα-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.

KW - Autophagy

KW - LAMP2a

KW - Parkinson’s disease

KW - VPS35

KW - α-synuclein

UR - http://www.scopus.com/inward/record.url?scp=84937677490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937677490&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.0042-15.2015

DO - 10.1523/JNEUROSCI.0042-15.2015

M3 - Article

C2 - 26203154

AN - SCOPUS:84937677490

VL - 35

SP - 10613

EP - 10628

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 29

ER -