Conditional expression of Parkinson's disease-related mutantα-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1

Xian Lin, Loukia Parisiadou, Carmelo Sgobio, Guoxiang Liu, Jia Yu, Lixin Sun, Hoon Shim, Xing Long Gu, Jing Luo, Cai Xia Long, Jinhui Ding, Yolanda Mateo, Patricia H. Sullivan, Ling Gang Wu, David S. Goldstein, David Lovinger, Huaibin Cai

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α-synuclein (α-syn) plays a prominent role in the degeneration of midbrain dopaminergic (mDA) neurons in Parkinson's disease (PD). However, only a few studies on α-syn have been performed in the mDA neurons in vivo, which may be attributed to a lack of α-syn transgenic mice that develop PD-like severe degeneration of mDA neurons. To gain mechanistic insights into the α-syn-induced mDA neurodegeneration, we generated a new line of tetracycline-regulated inducible transgenic mice that overexpressed the PD-related α-syn A53T missense mutation in the mDA neurons. Here we show that the mutant mice developed profound motor disabilities and robust mDA neurodegeneration, resembling some key motor and pathological phenotypes of PD. We also systematically examined the subcellular abnormalities that appeared in the mDA neurons of mutant mice and observed a profound decrease of dopamine release, the fragmentation of Golgi apparatus, and the impairments of autophagy/lysosome degradation pathways in these neurons. To further understand the specific molecular events leading to the α-syn-dependent degeneration of mDA neurons, we found that overexpression of α-syn promoted a proteasome-dependent degradation of nuclear receptor-related 1 protein (Nurr1), whereas inhibition of Nurr1 degradation ameliorated the α-syn-induced loss of mDA neurons. Given that Nurr1 plays an essential role in maintaining the normal function and survival of mDA neurons, our studies suggest that the α-syn-mediated suppression of Nurr1 protein expression may contribute to the preferential vulnerability of mDA neurons in the pathogenesis of PD.

Original languageEnglish (US)
Pages (from-to)9248-9264
Number of pages17
JournalJournal of Neuroscience
Issue number27
StatePublished - Jul 4 2012
Externally publishedYes

ASJC Scopus subject areas

  • General Neuroscience

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