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Articles, Cellular/Molecular

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 and Wen-Cheng Xiong
Journal of Neuroscience 22 July 2015, 35 (29) 10613-10628; DOI: https://doi.org/10.1523/JNEUROSCI.0042-15.2015
Fu-Lei Tang
1Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912,
2Charlie Norwood VA Medical Center, Augusta, Georgia 30912,
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Joanna R. Erion
1Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912,
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Yun Tian
1Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912,
3Department of Neurology, Xiang-Ya Hospital, Central South University, Changsha, Hunan, P.R. China 410083, and
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Wei Liu
1Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912,
4Department of Ophthalmology and Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, P.R. China 400042
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Dong-Min Yin
1Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912,
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Jian Ye
4Department of Ophthalmology and Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, P.R. China 400042
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Baisha Tang
3Department of Neurology, Xiang-Ya Hospital, Central South University, Changsha, Hunan, P.R. China 410083, and
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Lin Mei
1Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912,
2Charlie Norwood VA Medical Center, Augusta, Georgia 30912,
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Wen-Cheng Xiong
1Departments of Neuroscience and Regenerative Medicine and Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912,
2Charlie Norwood VA Medical Center, Augusta, Georgia 30912,
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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.

  • α-synuclein
  • autophagy
  • LAMP2a
  • Parkinson's disease
  • VPS35
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The Journal of Neuroscience: 35 (29)
Journal of Neuroscience
Vol. 35, Issue 29
22 Jul 2015
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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
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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
Journal of Neuroscience 22 July 2015, 35 (29) 10613-10628; DOI: 10.1523/JNEUROSCI.0042-15.2015

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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
Journal of Neuroscience 22 July 2015, 35 (29) 10613-10628; DOI: 10.1523/JNEUROSCI.0042-15.2015
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Keywords

  • α-synuclein
  • autophagy
  • LAMP2a
  • Parkinson's disease
  • VPS35

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