國家衛生研究院 NHRI:Item 3990099045/12607
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    題名: Downregulation of alpha-synuclein protein levels by an intracellular single-chain antibody
    其他題名: Downregulation of α-synuclein protein levels by an intracellular single-chain antibody
    作者: Chen, YH;Yu, SJ;Wu, KJ;Wang, YS;Tsai, HM;Liao, LW;Chen, S;Hsieh, W;Chen, H;Hsu, SC;Chen, ML;Hoffer, BJ;Wang, Y
    貢獻者: Center for Neuropsychiatric Research;National Institute of Infectious Diseases and Vaccinology
    摘要: BACKGROUND: Accumulation of alpha-synuclein (alphaSyn) in the dopaminergic neurons is a common pathology seen in patients with Parkinson's disease (PD). Overproduction of alphaSyn potentiates the formation of oligomeric alphaSyn aggregates and enhances dopaminergic neuron degeneration. Downregulating intracellular monomeric alphaSyn prevents the formation of alphaSyn oligomers and is a potential therapeutic strategy to attenuate the progression of PD. OBJECTIVE: The purpose of this study is to investigate the efficacy of gene delivery of alphaSyn-specific single-chain antibodies in vitro and in vivo. METHODS AND RESULTS: The plasmids for alphaSyn and selective antibodies (NAC32, D10, and VH14) were constructed and were transfected to HEK293 and SH-SY5Y cells. Co-expression of alphaSyn with NAC32, but not D10 or VH14, profoundly downregulated alphaSyn protein, but not alphaSyn mRNA levels in these cells. The interaction of alphaSyn and NAC32 antibody was next examined in vivo. Adeno-associated virus (AAV)-alphaSyn combined with AAV-NAC32 or AAV-sc6H4 (a negative control virus) were stereotactically injected into the substantia nigra of adult rats. AAV-NAC32 significantly reduced AAV-encoded alphaSyn levels in the substantia nigra and striatum and increased tyrosine hydroxylase immunoreactivity in the striatum. Also, in the animals injected with AAV-NAC32 alone, endogenous alphaSyn protein levels were significantly downregulated in the substantia nigra. CONCLUSION: Our data suggest that AAV-mediated gene transfer of NAC32 is a feasible approach for reducing the expression of target alphaSyn protein in brain.
    日期: 2020-03-11
    關聯: Journal of Parkinson's Disease. 2020 Mar 11;10(2):573-590.
    Link to: http://dx.doi.org/10.3233/jpd-191787
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1877-7171&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000526818700018
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85083041935
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