Proteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson's disease model.
Proteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson's disease model.
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DOI：
10.1038/s41531-018-0062-4
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Kordower JH
中科院分区：
文献类型：
--
作者：
Chatterjee D;Bhatt M;Butler D;De Genst E;Dobson CM;Messer A;Kordower JH
Therapeutics designed to target α-synuclein (α-syn) aggregation may be critical in halting the progression of pathology in Parkinson’s disease (PD) patients. Nanobodies are single-domain antibody fragments that bind with antibody specificity, but allow readier genetic engineering and delivery. When expressed intracellularly as intrabodies, anti-α-syn nanobodies fused to a proteasome-targeting proline, aspartate or glutamate, serine, and threonine (PEST) motif can modulate monomeric concentrations of target proteins. Here we aimed to validate and compare the in vivo therapeutic potential of gene therapy delivery of two proteasome-directed nanobodies selectively targeting α-syn in a synuclein overexpression-based PD model: VH14*PEST (non-amyloid component region) and NbSyn87*PEST (C-terminal region). Stereotaxic injections of adeno-associated viral 5-α-syn (AAV5-α-syn) into the substantia nigra (SN) were performed in Sprague–Dawley rats that were sorted into three cohorts based on pre-operative behavioral testing. Rats were treated with unilateral SN injections of vectors for VH14*PEST, NbSyn87*PEST, or injected with saline 3 weeks post lesion. Post-mortem assessments of the SN showed that both nanobodies markedly reduced the level of phosphorylated Serine-129 α-syn labeling relative to saline-treated animals. VH14*PEST showed considerable maintenance of striatal dopaminergic tone in comparison to saline-treated and NbSyn87*PEST-treated animals as measured by tyrosine hydroxylase immunoreactivity (optical density), DAT immunoreactivity (optical density), and dopamine concentration (high-performance liquid chromatography). Microglial accumulation and inflammatory response, assessed by stereological counts of Iba-1-labeled cells, was modestly increased in NbSyn87*PEST-injected rats but not in VH14*PEST-treated or saline-treated animals. Modest behavioral rescue was also observed, although there was pronounced variability among individual animals. These data validate in vivo therapeutic efficacy of vector-delivered intracellular nanobodies targeting α-syn misfolding and aggregation in synucleinopathies such as PD. Two nanobodies – fragments of antibodies – that target the highly conserved protein alpha-synuclein for degradation reduce neurotoxicity in a rat model of Parkinson’s Disease (PD). Misfolded aggregated alpha-synuclein is the major component of the characteristic protein deposits found in PD, Lewy bodies. Previous studies have shown that alpha-synuclein-binding nanobodies containing a peptide sequence that acts as a signal for protein degradation interfere with alpha-synuclein aggregation in neurons. Jeffrey Kordower at Rush University Medical Center in Chicago, USA, and colleagues have used viruses to deliver these nanobodies into the substantia nigra of rats overexpressing alpha-synuclein in this brain region. The nanobodies not only reduced alpha-synuclein aggregation, they also improved motor function. These findings highlight a promising approach for halting the progression of PD and other neurodegenerative diseases characterized by the accumulation of abnormal alpha-synuclein aggregates.
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影响因子：
16.6
作者：
Fusco, Giuliana;Pape, Tillmann;Stephens, Amberley D.;Mahou, Pierre;Costa, Ana Rita;Kaminski, Clemens F.;Schierle, Gabriele S. Kaminski;Vendruscolo, Michele;Veglia, Gianluigi;Dobson, Christopher M.;De Simone, Alfonso
通讯作者：
De Simone, Alfonso
影响因子：
4.8
作者：
Chandra, Goutam;Rangasamy, Suresh B.;Pahan, Kalipada
通讯作者：
Pahan, Kalipada
影响因子：
25
作者：
Chan KY;Jang MJ;Yoo BB;Greenbaum A;Ravi N;Wu WL;Sánchez-Guardado L;Lois C;Mazmanian SK;Deverman BE;Gradinaru V
通讯作者：
Gradinaru V
影响因子：
--
作者：
Bannas, Peter;Lenz, Alexander;Koch-Nolte, Friedrich
通讯作者：
Koch-Nolte, Friedrich
DOI：
10.1126/science.aam9080
发表时间：
2017-09-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Burbulla LF;Song P;Mazzulli JR;Zampese E;Wong YC;Jeon S;Santos DP;Blanz J;Obermaier CD;Strojny C;Savas JN;Kiskinis E;Zhuang X;Krüger R;Surmeier DJ;Krainc D
通讯作者：
Krainc D