Study Rationale: Alpha-synuclein is the main protein that aggregates and forms Lewy bodies, the hallmark histological characteristics of Parkinson disease (PD). Multiple experimental studies suggest that extracellular aggregates of alpha-synuclein can propagate from one cell to another, disseminating pathology in a process that resembles an infectious disease. Clearance of these aggregates is therefore expected to halt or even reverse PD pathology. KLK6 is an extracellular enzyme, produced in the brain, that has been shown to cleave alpha-synuclein aggregates with high specificity, while cleaving only a limited number of other human proteins.
Hypothesis: Given the specificity KLK6 displays for alpha-synuclein and their co-localization in the brain, we hypothesize that KLK6 could be a modulator for the clearance and turnover of alpha-synuclein aggregates — and a potential target for new PD therapeutics.
Study Design: We will test the effect of KLK6 on alpha-synuclein cleavage and aggregation by means of established methods both in test tubes and in cells and preclinical PD models. Solutions containing alpha-synuclein will be cleaved by KLK6. Then, the KLK6 cleaved alpha-synuclein will be examined to see whether it can seed alpha-synuclein aggregation and transmit pathology in cell culture and mouse models. The role of KLK6 on alpha-synuclein turnover and PD pathology will be further investigated by viral transduction of KLK6 expression in an established PD mouse model. This study will provide the grounds for the therapeutic exploitation of our target.
Impact on Diagnosis/Treatment of Parkinson’s disease: The results of the present study will define the role of the KLK6 enzyme on extracellular alpha-synuclein turnover and facilitate the development of new therapeutic strategies that will aim to increase the clearance of alpha-synuclein.
Next Steps for Development: After demonstrating that KLK6 regulates alpha-synuclein turnover, we will explore approaches for boosting KLK6 activity in the brain, including delivering KLK6 to the brain using nanoparticles (including liposomes) or KLK6-fusion proteins that can penetrate the blood-brain barrier.