title: Conditional expression of Parkinson's disease-related mutant α-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1.
abstract: 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.
authors: Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Xian
authors: X
authors: Lin
authors: Loukia
authors: L
authors: Parisiadou
authors: Carmelo
authors: C
authors: Sgobio
authors: Guoxiang
authors: G
authors: Liu
authors: Jia
authors: J
authors: Yu
authors: Lixin
authors: L
authors: Sun
authors: Hoon
authors: H
authors: Shim
authors: Xing-Long
authors: XL
authors: Gu
authors: Jing
authors: J
authors: Luo
authors: Cai-Xia
authors: CX
authors: Long
authors: Jinhui
authors: J
authors: Ding
authors: Yolanda
authors: Y
authors: Mateo
authors: Patricia H
authors: PH
authors: Sullivan
authors: Ling-Gang
authors: LG
authors: Wu
authors: David S
authors: DS
authors: Goldstein
authors: David
authors: D
authors: Lovinger
authors: Huaibin
authors: H
authors: Cai
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D018450:Disease Progression; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D061251:Primary Cell Culture; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
chemical_list: C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; C497605:Snca protein, mouse; D051844:alpha-Synuclein