Dopamine neurons exhibit emergent glutamatergic identity in Parkinson's disease

被引:23
作者
Steinkellner, Thomas [1 ,2 ]
Conrad, William S. [1 ]
Kovacs, Imre [1 ]
Rissman, Robert A. [1 ,3 ]
Lee, Edward B. [4 ]
Trojanowski, John Q. [4 ]
Freyberg, Zachary [5 ,6 ]
Roy, Subhojit [1 ,7 ]
Luk, Kelvin C. [4 ]
Lee, Virginia M. [4 ]
Hnasko, Thomas S. [1 ,3 ]
机构
[1] Univ Calif San Diego, Dept Neurosci, 9500 Gilman Dr, La Jolla, CA 92093 USA
[2] Med Univ Vienna, Ctr Physiol & Pharmacol, Inst Pharmacol, Waehringerstr 13A, A-1090 Vienna, Austria
[3] VA San Diego Healthcare Syst, Res Serv, San Diego, CA USA
[4] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[5] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA
[6] Univ Pittsburgh, Dept Cell Biol, Pittsburgh, PA USA
[7] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA
基金
奥地利科学基金会;
关键词
dopamine; vesicular glutamate transporter 2; selective vulnerability; Parkinson's disease; alpha-synuclein; ALPHA-SYNUCLEIN; SELECTIVE VULNERABILITY; SUBSTANTIA-NIGRA; CORELEASE; NEURODEGENERATION; OVEREXPRESSION; TRANSMISSION;
D O I
10.1093/brain/awab373
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Loss of midbrain dopamine neurons causes the cardinal symptoms of Parkinson's disease. However, not all dopamine neurons are equally vulnerable and a better understanding of the cell-type specific properties relating to selective dopamine neuron degeneration is needed. Most midbrain dopamine neurons express the vesicular glutamate transporter VGLUT2 during development and a subset continue to express low levels of VGLUT2 in adulthood, enabling the co-release of glutamate. Moreover, VGLUT2 expression in dopamine neurons can be neuroprotective since its genetic disruption was shown to sensitize dopamine neurons to neurotoxins. Here, we show that in response to toxic insult, and in two distinct models of alpha-synuclein stress, VGLUT2 dopamine neurons were resilient to degeneration. Dopamine neurons expressing VGLUT2 were enriched whether or not insult induced dopamine neuron loss, suggesting that while VGLUT2 dopamine neurons are more resilient, VGLUT2 expression can also be transcriptionally upregulated by injury. Finally, we observed that VGLUT2 expression was enhanced in surviving DA neurons from post-mortem Parkinson's disease individuals. These data indicate that emergence of a glutamatergic identity in dopamine neurons may be part of a neuroprotective response in Parkinson's disease.
引用
收藏
页码:879 / 886
页数:8
相关论文
共 50 条
[31]   Astrocytes and Therapeutics for Parkinson's Disease [J].
Rappold, Phillip M. ;
Tieu, Kim .
NEUROTHERAPEUTICS, 2010, 7 (04) :413-423
[32]   A Molecular Basis for the Increased Vulnerability of Substantia Nigra Dopamine Neurons in Aging and Parkinson's Disease [J].
Chan, C. Savio ;
Gertler, Tracy S. ;
Surmeier, D. James .
MOVEMENT DISORDERS, 2010, 25 (03) :S63-S70
[33]   IMPACT OF METHAMPHETAMINE ON DOPAMINE NEURONS IN PRIMATES IS DEPENDENT ON AGE: IMPLICATIONS FOR DEVELOPMENT OF PARKINSON'S DISEASE [J].
Morrow, B. A. ;
Roth, R. H. ;
Redmond, D. E. ;
Elsworth, J. D. .
NEUROSCIENCE, 2011, 189 :277-285
[34]   5-S-cysteinyl-dopamine, a neurotoxic endogenous metabolite of dopamine: Implications for Parkinson's disease [J].
Badillo-Ramirez, Isidro ;
Saniger, Jose M. ;
Rivas-Arancibia, Selva .
NEUROCHEMISTRY INTERNATIONAL, 2019, 129
[35]   Molecular determinants of selective dopaminergic vulnerability in Parkinson's disease: an update [J].
Brichta, Lars ;
Greengard, Paul .
FRONTIERS IN NEUROANATOMY, 2014, 8
[36]   Parkinson's disease α-synuclein mutations exhibit defective axonal transport in cultured neurons [J].
Saha, AR ;
Hill, J ;
Utton, MA ;
Asuni, AA ;
Ackerley, S ;
Grierson, AJ ;
Miller, CC ;
Davies, AM ;
Buchman, VL ;
Anderton, BH ;
Hanger, DP .
JOURNAL OF CELL SCIENCE, 2004, 117 (07) :1017-1024
[37]   Role of dopamine in the pathophysiology of Parkinson’s disease [J].
Zhi Dong Zhou ;
Ling Xiao Yi ;
Dennis Qing Wang ;
Tit Meng Lim ;
Eng King Tan .
Translational Neurodegeneration, 12
[38]   PUERARIN PROTECTS DOPAMINERGIC NEURONS IN PARKINSON'S DISEASE MODELS [J].
Zhang, X. ;
Xiong, J. ;
Liu, S. ;
Wang, L. ;
Huang, J. ;
Liu, L. ;
Yang, J. ;
Zhang, G. ;
Guo, K. ;
Zhang, Z. ;
Wu, P. ;
Wang, D. ;
Lin, Z. ;
Xiong, N. ;
Wang, T. .
NEUROSCIENCE, 2014, 280 :88-98
[39]   A specific survival response in dopamine neurons at most risk in Parkinson's disease [J].
Murase, Sachiko ;
McKay, Ronald D. .
JOURNAL OF NEUROSCIENCE, 2006, 26 (38) :9750-9760
[40]   Asymmetric Presynaptic Depletion of Dopamine Neurons in a Drosophila Model of Parkinson's Disease [J].
Zhang, Jiajun ;
Lentz, Lucie ;
Goldammer, Jens ;
Iliescu, Jessica ;
Tanimura, Jun ;
Riemensperger, Thomas Dieter .
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2023, 24 (10)