Treatment with Trehalose Prevents Behavioral and Neurochemical Deficits Produced in an AAV α-Synuclein Rat Model of Parkinson’s Disease
- 1.3k Downloads
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.
KeywordsParkinson’s disease α-Synuclein Trehalose DA Autophagy
This work was supported by grants from the National Foundation of Natural Science of China (No.81071018 and No.81371413), key project from Science and Technology Commission of Shanghai Municipality (13JC1401103), and project of Shanghai Municipal Commission of Health (XBR2013088). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Dr. Shun Yu from Xuanwu Hospital of the Capital University of Medical Sciences, Beijing, China, for kindly providing the human α-synuclein antibody for immunofluorescence.
Conflict of interest
The authors declare that they have no competing interests.
WJ, Koprich JB, and Brotchie JM designed this study. HQ, WY, and YWB performed this study, analyzed data, and wrote the manuscript. XBG assisted in behavioral analysis. All authors discussed the results and provided comments on the manuscript. All authors read and approved the final manuscript.
- 20.Koprich JB, Johnston TH, Reyes MG, Sun X, Brotchie JM (2010) Expression of human A53T alpha-synuclein in the rat substantia nigra using a novel AAV1/2 vector produces a rapidly evolving pathology with protein aggregation, dystrophic neurite architecture and nigrostriatal degeneration with potential to model the pathology of Parkinson’s disease. Mol Neurodegener 5:43CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B et al (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 118:2190–2199PubMedPubMedCentralGoogle Scholar
- 40.Chu Y, Dodiya H, Aebischer P, Olanow CW, Kordow-er JH (2009) Alterations in lysosomal and proteasomal markers in Parkinson’s disease: relationship to alpha-synuclein inclusions. Neurobiol Dis 35:385–398Google Scholar