TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson's disease via CNTF

Jin H Nam; Eun S Park; So-Yoon Won; Yu A Lee; Kyoung I Kim; Jae Y Jeong; Jeong Y Baek; Eun J Cho; Minyoung Jin; Young C Chung; Byoung D Lee; Sung Hyun Kim; Eung-Gook Kim; Kyunghee Byun; Bonghee Lee; Dong Ho Woo; C Justin Lee; Sang R Kim; Eugene Bok; Yoon-Seong Kim; Tae-Beom Ahn; Hyuk Wan Ko; Saurav Brahmachari; Olga Pletinkova; Juan C Troconso; Valina L Dawson; Ted M Dawson; Byung K Jin

doi:10.1093/brain/awv297

TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson's disease via CNTF

Brain. 2015 Dec;138(Pt 12):3610-22. doi: 10.1093/brain/awv297. Epub 2015 Oct 21.

Authors

Jin H Nam¹, Eun S Park¹, So-Yoon Won², Yu A Lee¹, Kyoung I Kim¹, Jae Y Jeong¹, Jeong Y Baek¹, Eun J Cho¹, Minyoung Jin¹, Young C Chung¹, Byoung D Lee¹, Sung Hyun Kim¹, Eung-Gook Kim², Kyunghee Byun³, Bonghee Lee³, Dong Ho Woo⁴, C Justin Lee⁴, Sang R Kim⁵, Eugene Bok⁶, Yoon-Seong Kim⁷, Tae-Beom Ahn⁸, Hyuk Wan Ko¹, Saurav Brahmachari⁹, Olga Pletinkova¹⁰, Juan C Troconso¹¹, Valina L Dawson¹², Ted M Dawson¹³, Byung K Jin¹⁴

Affiliations

¹ 1 Department of Biochemistry and Molecular Biology, Department of Neuroscience, Neurodegeneration Control Research Centre, School of Medicine Kyung Hee University, Seoul 130-701, Korea.
² 2 Department of Biochemistry and Signaling Disorder Research Centre, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea.
³ 3 Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon 406-840, Korea.
⁴ 4 Center for Neuroscience and Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul 130-701, Korea.
⁵ 5 School of Life Sciences, BK21 Plus KNU Creative Bio Research Group, Kyungpook National University, Daegu 702-701, Korea.
⁶ 1 Department of Biochemistry and Molecular Biology, Department of Neuroscience, Neurodegeneration Control Research Centre, School of Medicine Kyung Hee University, Seoul 130-701, Korea 6 Burnett School of Biomedical Sciences, College of Medicine University of Central Florida, FL 32827, USA.
⁷ 6 Burnett School of Biomedical Sciences, College of Medicine University of Central Florida, FL 32827, USA.
⁸ 7 Department of Neurology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
⁹ 8 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 9 Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 10 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
¹⁰ 11 Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
¹¹ 9 Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 11 Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
¹² 8 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 9 Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 12 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 13 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 14 Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
¹³ 8 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 9 Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 10 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 12 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 14 Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA 15 Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA.
¹⁴ 1 Department of Biochemistry and Molecular Biology, Department of Neuroscience, Neurodegeneration Control Research Centre, School of Medicine Kyung Hee University, Seoul 130-701, Korea bkjin@khu.ac.kr.

Abstract

Currently there is no neuroprotective or neurorestorative therapy for Parkinson's disease. Here we report that transient receptor potential vanilloid 1 (TRPV1) on astrocytes mediates endogenous production of ciliary neurotrophic factor (CNTF), which prevents the active degeneration of dopamine neurons and leads to behavioural recovery through CNTF receptor alpha (CNTFRα) on nigral dopamine neurons in both the MPP(+)-lesioned or adeno-associated virus α-synuclein rat models of Parkinson's disease. Western blot and immunohistochemical analysis of human post-mortem substantia nigra from Parkinson's disease suggests that this endogenous neuroprotective system (TRPV1 and CNTF on astrocytes, and CNTFRα on dopamine neurons) might have relevance to human Parkinson's disease. Our results suggest that activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and that it is a novel therapeutic target for the treatment of Parkinson's disease.

Keywords: Parkinson’s disease; TRPV1; astrocyte; ciliary neurotrophic factor (CNTF); dopamine neurons.

Publication types

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

MeSH terms

Animals
Astrocytes / metabolism*
Ciliary Neurotrophic Factor / metabolism*
Ciliary Neurotrophic Factor Receptor alpha Subunit / metabolism
Disease Models, Animal
Dopaminergic Neurons / metabolism*
Dopaminergic Neurons / pathology
Female
Humans
Nerve Regeneration
Neuroprotection*
Parkinson Disease / metabolism*
Parkinson Disease / pathology*
Parkinson Disease / physiopathology
Rats
Substantia Nigra / cytology
Substantia Nigra / metabolism*
Substantia Nigra / pathology
TRPV Cation Channels / metabolism

Substances

Ciliary Neurotrophic Factor
Ciliary Neurotrophic Factor Receptor alpha Subunit
TRPV Cation Channels
TRPV1 receptor

Grants and funding

P50NS038377/NS/NINDS NIH HHS/United States