This grant builds upon the research from a prior grant: PARK14: Validation of a New Pre-clinical Model of Age-dependent PD
Objective/Rationale:
Mutations in the PARK14 gene are associated with Parkinson’s disease (PD), but its role in idiopathic PD is presently unknown. Recently we identified a role of PARK14 as a master regulator of calcium ion (Ca2+) signaling and found that its impairment initiates events that are detrimental to dopamine neurons. The objective of this project is to translate our discoveries from pre-clinical models to human idiopathic PD to determine if dysfunction of PARK14-dependent Ca2+ signaling could be found in the cells of idiopathic PD patients.
Project Description:
PARK14-dependent Ca2+ signaling will be studied using advanced imaging and molecular techniques in skin fibroblasts from idiopathic PD and control donors, as well as in induced pluripotent stem cell-derived dopaminergic neurons.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Successful translation of our findings and validation of the novel role of PARK14-dependent Ca2+ signaling in PD will unveil new targets for development of novel disease-modifying treatments.
Anticipated Outcome:
This study will establish a new cascade of pathological PARK14-dependent Ca2+ signaling events as a trigger of PD.
Final Outcome
In this study, we aimed to determine whether Ca2+ signaling dependent on the PARK14 gene is dysfunctional in the cells of people with idiopathic Parkinson's disease (PD). PARK14-dependent Ca2+ signaling -- chains of chemical reactions taking place inside the cell and involving Ca2+ -- was found strongly associated with specific defect in the PARK14 gene. This association was previously unknown.
Our studies revealed a significant reduction in the expression of PLA2g6, a variant of the PARK14 gene, and in the ability of the cell to maintain Ca2+ balance. This can be viewed as a previously unknown sign of idiopathic PD as well as inherited PD associated with specific changes -- mutations -- in the PARK14 gene. These changes were detected in the skin cells obtained from a small group of people with idiopathic PD via skin biopsy.
We also developed a pre-clinical model that does not express PLA2g6. The model displays pathological changes that we found in the cells of people with idiopathic PD. This model also has characteristic age-dependent PD-like features that closely resemble the features of idiopathic PD in older people.
The results of all these studies further confirm the newly discovered features of idiopathic PD associated with PARK14 mutations. Our findings open exciting possibilities for development of new, fundamentally different strategies for diagnosis and potential treatment of idiopathic PD.
October 2016
Publications:
Zhou Q, Yen A, Rymarczyk G, et al. Impairment of PARK14-dependent Ca2+ signaling is a novel trigger for autophagic dysfunction and Parkinson's Disease. Nat Commun. 2016;7:10332.
Oral presentations:
Bolotina VM. Impairment of PARK14-dependent Ca2+ signaling is a novel determinant of Parkinson's Disease. Presented at: Society for Neuroscience Annual Meeting; October 17-21, 2015; Chicago, IL.
Yen A, Mostoslavsky G, Bolotina VM. Genetic impairment of the store-operated Ca2+ signaling triggers autophagic dysfunction in iPSC-derived neurons from PARK14/PLA2g6ex2KO and Orai1KO mouse models. Society for Neuroscience Annual Meeting; November 16-19, 2016; San Diego, CA.
Posters:
iPSC-Derived dopaminergic neurons reveal new mechanism of vulnerability underlying Parkinson's Disease. Poster presented at: Society for Neuroscience Annual Meeting; October 17-21, 2015; Chicago, IL.
Impairment of PARK14-dependent Ca2+ signaling is a novel trigger for autophagic dysfunction and Parkinson's Disease. Poster presented at: Gordon Research Conference; 2015.