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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.

PROVIDER: S-EPMC7895943 | BioStudies |

REPOSITORIES: biostudies

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