Parkinson's disease (PD) is a common neurodegenerative disorder that affects millions of people worldwide, and there is no treatment that can halt its progression. Neuronal death are due to the accumulation and aggregation of a-synuclein. All clinical trials of antibodies against a-synuclein failed to improve the disease. Therefore, there is an urgent need to find agents that can treat PD and other a-synucleinopathies, such as dementia with Lewy bodies (DLB). To this end, we have developed a a-synuclein cell-penetrating peptide (TAT-a-syn90-108) that works as a decoy peptide, preventing a-synuclein SUMOylation and consequently enhancing its degradation. We found that this decoy peptide significantly reduced the levels and pathology of a-synuclein in neurons. It also decreased endogenous levels of a-synuclein in mouse brains when administered intraperitoneally, suggesting that the decoy peptide enters the CNS and exerts an immediate and robust effect. Most importantly, we found that it reduced a-synuclein pathology when administered intraperitoneally into the PD mouse model of a-synuclein pre-formed fibrils (a-SynPFF). We now plan to investigate the effect of the decoy peptide in additional PD mouse models to extend the in vivo experiments and determine the effective peptide concentration that can be used in clinical trials. We have extensive knowledge on studying the cellular pathways that lead to the degradation and accumulation of a-synuclein in PD patients. We have the appropriate expertise and facilities to study the effect of the decoy peptide on the pathology of PD mice and thus develop a new agent to treat PD and other a-synucleinopathies.