Tat-βsyn-degron, an α-synuclein knockdown peptide, integrates three domains: the HIV-1 Tat plasma membrane transduction domain, an α-synuclein binding domain (βsyn) representing amino acids 36-45 of β-synuclein, and a proteasomal targeting domain (degron). It effectively binds to recombinant α-synuclein, demonstrating a significant reduction in α-synuclein levels in primary rat cortical neuron cultures.

Administrating Tat-βsyn-degron at 40 mg/kg reduces α-synuclein levels in the brains of M38 transgenic mice overexpressing human A53T mutant α-synuclein. It also diminishes phosphorylated α-synuclein levels in the substantia nigra and the pons, alongside neuroinflammation in mice exposed to α-synuclein preformed fibrils, simulating spreading synucleinopathy. Furthermore, at a dosage of 6 µmol/kg intraperitoneally, Tat-βsyn-degron ameliorates dopaminergic neuron loss and improves motor deficits in mice suffering from MPTP-induced Parkinson’s disease, underscoring its potential therapeutic benefit.