PARK14: Validation of a New Pre-clinical Model of Age-dependent PD

Objective/Rationale:            
The gene PARK 14 (PLA2g6) is expressed in human brain, and numerous mutations in this gene were found to be associated with PD, but the mechanism of such association is presently unknown. Recently we identified a new role of PARK14 as a master regulator of the calcium ion Ca²⁺ mechanism that is essential for timely refilling of intracellular Ca²⁺ stores. The role of this mechanism in PD is unknown, but we believe that its impairment can lead to Ca²⁺ depletion, mitochondrial dysfunction and oxidative stress, which are all detrimental to dopaminergic neurons, and are the hallmarks of human PD.

Project Description:             
To test this idea we created a novel transgenic pre-clinical model in which the specific Ca²⁺ signaling function of PARK14 is genetically impaired. Preliminary studies showed that these models develop significant loss of dopaminergic neurons and age-dependent motor dysfunction that can be reversed by levodopa and resemble human PD. The aim of this project is to validate a new PARK14-dependent mechanism leading to PD through in vivo characterization of the PD-like presentation of the PARK14 knock-out model and in vitro characterization of the effects of PD-associated PARK14 mutations. The proposed studies will provide comprehensive characterization of the novel PARK14 model and validate its relevance to human PD. 

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Successful validation of a new PARK14 knock-out model promises to give important insights into age-dependent PD, and could be used for 1) identification of the events preceding the onset of the clinical symptoms that could be further tested and used as early markers of PD in humans, 2) testing existing drugs or candidate drugs that could slow, or prevent PD development, 3) development of new drugs and approaches targeting PARK14 and downstream processes for PD prevention and treatment.

Anticipated Outcome:          
This study will unveil a new cascade of pathological events that can be triggered by genetic mutations in PARK14. It will validate a novel model of age-dependent PD, which promises to provide unique opportunities for a) detection of PD markers in preclinical stage, b) testing new therapeutic strategies, and c) development of new drugs that may interfere with age-dependent loss of dopaminergic neurons and severe PD-like motor dysfunction.