Dataset Information

Development of an ?-synuclein knockdown peptide and evaluation of its efficacy in Parkinson's disease models.

ABSTRACT: Convincing evidence supports the premise that reducing ?-synuclein levels may be an effective therapy for Parkinson's disease (PD); however, there has been lack of a clinically applicable ?-synuclein reducing therapeutic strategy. This study was undertaken to develop a blood-brain barrier and plasma membrane-permeable ?-synuclein knockdown peptide, Tat-?syn-degron, that may have therapeutic potential. The peptide effectively reduced the level of ?-synuclein via proteasomal degradation both in cell cultures and in animals. Tat-?syn-degron decreased ?-synuclein aggregates and microglial activation in an ?-synuclein pre-formed fibril model of spreading synucleinopathy in transgenic mice overexpressing human A53T ?-synuclein. Moreover, Tat-?syn-degron reduced ?-synuclein levels and significantly decreased the parkinsonian toxin-induced neuronal damage and motor impairment in a mouse toxicity model of PD. These results show the promising efficacy of Tat-?syn-degron in two different animal models of PD and suggest its potential use as an effective PD therapeutic that directly targets the disease-causing process.

SUBMITTER: Jin JW

PROVIDER: S-EPMC7895943 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Development of an α-synuclein knockdown peptide and evaluation of its efficacy in Parkinson's disease models.

Jin Jack Wuyang JW Fan Xuelai X Del Cid-Pellitero Esther E Liu Xing-Xing XX Zhou Limin L Dai Chunfang C Gibbs Ebrima E He Wenting W Li Hongjie H Wu Xiaobin X Hill Austin A Leavitt Blair R BR Cashman Neil N Liu Lidong L Lu Jie J Durcan Thomas M TM Dong Zhifang Z Fon Edward A EA Wang Yu Tian YT

Communications biology 20210219 1

Convincing evidence supports the premise that reducing α-synuclein levels may be an effective therapy for Parkinson's disease (PD); however, there has been lack of a clinically applicable α-synuclein reducing therapeutic strategy. This study was undertaken to develop a blood-brain barrier and plasma membrane-permeable α-synuclein knockdown peptide, Tat-βsyn-degron, that may have therapeutic potential. The peptide effectively reduced the level of α-synuclein via proteasomal degradation both in ce ...[more]

PMID: 33608634

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Project description:Importance. Biological markers of Parkinson’s disease are essential for achieving disease modification. Objective. To determine the association of SNCA blood transcript levels with prevalence of Parkinson’s disease. Background. The SNCA locus is preferentially transcribed in neurons and blood cells. Non-coding genetic variants and neuronal aggregates of α-synuclein protein associate this locus with sporadic Parkinson’s disease and suggest a potential role for abnormal SNCA transcription in the disease mechanism. Here we investigated variation in intracellular SNCA gene expression and SNCA transcript isoform abundance in circulating blood cells of cases with PD and controls in a network of biobanks that represent regional, national, and international populations. Design, Setting, Participants. Three cross-sectional, case-control studies nested in observational biomarker studies. 222 cases with early-stage clinical PD and 183 controls were enrolled from 2005 to 2010 in the Harvard Biomarker Study (HBS) at two Harvard-affiliated tertiary care centers. 76 cases with dopamine transporter imaging (DAT)-confirmed PD and 42 controls were enrolled between August 2007 and December 2008 in the Blood α-Synuclein, Gene Expression and Smell Testing as Diagnostic and Prognostic Biomarkers in Parkinson’s Disease Study (PROBE) study from 22 US tertiary care centers. 202 DAT-confirmed cases with de novo PD and 138 controls were enrolled in the Parkinson’s Progression Markers Initiative (PPMI) between July 2010 and November 2012 from 22 US and international tertiary care centers. Main Outcome Measures. Association of intracellular SNCA transcript abundance with PD estimated on analog and digital expression platforms. Results. Reduced levels of SNCA transcripts were associated with early-stage clinical PD, neuroimaging-confirmed PD, and untreated, neuroimaging-confirmed PD in accessible, peripheral blood cells from a total of 863 individuals. SNCA expression was reduced by 17%, 22%, and 16% in cases compared to controls in the HBS, PROBE, and PPMI study with P values of 0.004, 0.025, and 0.018, respectively, after adjusting for clinical, hematological, and processing covariates. Specific SNCA transcripts with long 3’ untranslated regions (UTR) and those skipping exon 5 are implicated in the accumulation and mitochondrial targeting of α-synuclein protein in Parkinson’s pathology. These transcript isoforms were linked to PD through digital expression analysis. Individuals in the lowest quartile of SNCA expression values had covariate-adjusted odds ratios for PD of 2.14 (95% C. I. 1.1-4.1), 4.5 (95% C. I. 1.3-15), and 2.1 (1.1-4.0) compared to individuals in the highest quartile of expression values in the HBS, PROBE, and PPMI study, respectively. Conclusions and Relevance. Reduced levels of SNCA expression, particularly of disease-relevant transcripts with extended 3’ UTR or exon 5 skipping, are associated with early-stage PD. These findings support a potential role for SNCA as a transcriptional marker of PD and may have implications for patient stratification and risk assessment.

Dataset Information

Development of an ?-synuclein knockdown peptide and evaluation of its efficacy in Parkinson's disease models.

Publications

Development of an α-synuclein knockdown peptide and evaluation of its efficacy in Parkinson's disease models.

Similar Datasets

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