Objective/Rationale:
Alpha-synuclein is a protein critically involved in the pathogenesis of Parkinson’s disease. Growing evidence link alpha-synuclein pathogenesis in PD and brain lipid metabolism. In this proposal we suggest to examine aspects of peroxisome function in relation to PD. Peroxisomes are cellular organelles crucial in various lipid metabolic activities and peroxisomal dysfunction, may lead among other insults, to neurodegeneration. Specifically, we suggest to examine whether peroxisome proliferation will abrogate alpha-synuclein toxicity leading to PD.
Project Description:
We basically suggest two approaches to enhance peroxisomal activities. The first is to over express genes involved in peroxisomal proliferation in naïve and alpha-synuclein over expressing cells. These genes belong to the Peroxisome Proliferator Activated Receptors (PPARs). Specifically, three such member are known, Ppara, Pparb/d and Pparg. The second approach is to use specific PPAR agonists and pharmacologically activate endogenous PPAR activity in naïve and alpha-synuclein neuronal models. We intend to determine whether enhanced Peroxisomal proliferation obtained by the activation of Ppar genes (either exogenous or endogenous) will result in inhibited molecular or cellular signs for alpha-synuclein-related toxicity. Including alpha-synuclein oligomerization, phosphorylation, aggregation, inclusion formation and cell viability.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
PPAR agonists are approved drugs and commonly used in type II diabetes. Importantly, PPAR agonists were recently shown to prevent neurodegeneration in cell culture and animal models. The agonists were specifically shown to control certain harmful factors in a PD model, consisting on the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, to the best of our knowledge, the effects of PPAR agonists were not tested on alpha-synuclein-related neurodegeneration or in relation to brain lipid metabolism.
Anticipated Outcome:
We anticipate that through the results obtained by the experiments suggested herein, we will improve our understanding regarding the potential role of peroxisomes in PD. More importantly, we hope to be able to determine whether Ppar agonists such as pioglitazone or WY14643, may be considered as a potential novel therapeutic strategy.
Final Outcome
Dr. Sharon was able to identify the involvement of certain peroxisomal pathways in alpha-synuclein pathogenesis in cultured dopaminergic cells and to validate these findings in vivo.