title: Treatment with Trehalose Prevents Behavioral and Neurochemical Deficits Produced in an AAV α-Synuclein Rat Model of Parkinson's Disease.
abstract: The accumulation of misfolded α-synuclein in dopamine (DA) neurons is believed to be of major importance in the pathogenesis of Parkinson's disease (PD). Animal models of PD, based on viral-vector-mediated over-expression of α-synuclein, have been developed and show evidence of dopaminergic toxicity, providing us a good tool to investigate potential therapies to interfere with α-synuclein-mediated pathology. An efficient disease-modifying therapeutic molecule should be able to interfere with the neurotoxicity of α-synuclein aggregation. Our study highlighted the ability of an autophagy enhancer, trehalose (at concentrations of 5 and 2% in drinking water), to protect against A53T α-synuclein-mediated DA degeneration in an adeno-associated virus serotype 1/2 (AAV1/2)-based rat model of PD. Behavioral tests and neurochemical analysis demonstrated a significant attenuation in α-synuclein-mediated deficits in motor asymmetry and DA neurodegeneration including impaired DA neuronal survival and DA turnover, as well as α-synuclein accumulation and aggregation in the nigrostriatal system by commencing 5 and 2% trehalose at the same time as delivery of AAV. Trehalose (0.5%) was ineffective on the above behavioral and neurochemical deficits. Further investigation showed that trehalose enhanced autophagy in the striatum by increasing formation of LC3-II. This study supports the concept of using trehalose as a novel therapeutic strategy that might prevent/reverse α-synuclein aggregation for the treatment of PD.
authors.affiliation: Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, China.|Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.affiliation: Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: James B
authors.initials: JB
authors.lastname: Koprich
authors.affiliation: Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Wen-bo
authors.initials: WB
authors.lastname: Yu
authors.affiliation: Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
authors.forename: Bao-guo
authors.initials: BG
authors.lastname: Xiao
authors.affiliation: Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. brotchie@uhnres.utoronto.ca.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
authors.affiliation: Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, China. wangjian336@hotmail.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D000229:Dependovirus / Q000378:metabolism*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D005121:Extremities / Q000473:pathology; D005260:Female; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D014199:Trehalose / Q000494:pharmacology / Q000627:therapeutic use*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D008869:Microtubule-Associated Proteins; D014199:Trehalose; D014446:Tyrosine 3-Monooxygenase; D051844:alpha-Synuclein; C526109:Anxa3 protein, rat
keywords: Autophagy; DA; Parkinson’s disease; Trehalose; α-Synuclein