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Development of a small alpha-synuclein-knockdown peptide as a potential therapy for Parkinson’s disease

University of British Columbia

Accumulating evidence supports the premise that reducing α-synuclein levels may be an effective and specific therapy for Parkinson’s disease. To date, a clinically applicable α-synuclein reducing therapeutic strategy has yet to be developed. To remedy this, I developed a blood brain barrier and plasma membrane-permeable α-synuclein knockdown peptide that may have therapeutic potentials. By modifying a peptide-based method that was recently developed in our lab to rapidly and reversibly decrease the levels of endogenous proteins, I developed an α-synuclein knockdown peptide, Tat-βsyn-degron, and tested its specificity and efficacy in reducing the level of α-synuclein and its neuroprotective efficacy in well-characterized cellular and animal models of Parkinson’s disease. I found that the peptide effectively reduced the level of α-synuclein via proteasomal degradation both in cell cultures and in freely moving animals. More importantly, the peptide-induced α-synuclein reduction was associated with a significant decrease in parkinsonian toxin-induced neuronal damage and motor impairment in an animal model of Parkinson’s disease. These results suggest that targeted degradation of α-synuclein using the Tat-βsyn-degron peptide represents a novel, specific and effective therapeutic strategy for reversing a core cellular mechanism contributing to Parkinson’s disease.

Text

2016-08-10

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/58717

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/