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

Commun Biol. 2021 Feb 19;4(1):232. doi: 10.1038/s42003-021-01746-6.

Abstract

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 cell cultures and in animals. Tat-βsyn-degron decreased α-synuclein aggregates and microglial activation in an α-synuclein pre-formed fibril model of spreading synucleinopathy in transgenic mice overexpressing human A53T α-synuclein. Moreover, Tat-βsyn-degron reduced α-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-βsyn-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / pharmacology*
  • Behavior, Animal / drug effects
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / pathology
  • Brain / physiopathology
  • Disease Models, Animal
  • Down-Regulation
  • HEK293 Cells
  • Humans
  • MPTP Poisoning / drug therapy*
  • MPTP Poisoning / genetics
  • MPTP Poisoning / metabolism
  • MPTP Poisoning / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Mutation
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Parkinson Disease / physiopathology
  • Peptides / pharmacology*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Rats
  • Rats, Sprague-Dawley
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • Antiparkinson Agents
  • Peptides
  • SNCA protein, human
  • Snca protein, mouse
  • alpha-Synuclein
  • Proteasome Endopeptidase Complex

Grants and funding