Objective/Rationale:
Alpha-synuclein plays a prominent role in Parkinson’s disease and identifying valid targets to ameliorate the neurodegenerative effects of alpha-synuclein is a major therapeutic endeavor. ATP13a2 / PARK9 is a strong candidate for a PD therapeutic target as a dose sensitive modifier of alpha-synuclein induced neurodegeneration. Mutations in ATP13a2 result in a juvenile onset form of recessive Parkinsonism. ATP13a2 is most highly expressed in PD sensitive regions of the brain and in the sporadic form of PD, surviving dopaminergic neurons in this region express ATP13a2 at 10-fold higher levels. Previous work identified that elevated ATP13A2 expression provides a robust suppression of toxicity associated with elevated alpha-synuclein levels in a range of PD models including pre-clinical model primary DA neurons. We intend to test in a pre-clinical model if modulation of ATP13a2 levels will modify alpha-synuclein dependent neurodegeneration.
Project Description:
The Thy1-alphaSyn pre-clinical model has been engineered to express human alpha-synuclein to levels that cause neurodegeneration which recapitulate features characteristic of PD including motor and olfactory defects in addition to alpha-synuclein deposition. The validation of ATP13a2 as a dose sensitive modulator of alpha-synuclein dependent neurodegeneration in the Thy1-alphaSyn pre-clinical model will be tested by determining if reduced ATP13a2 expression exacerbates the alpha-synuclein dependent defects. Conversely, elevated ATP13a2 expression will be examined for amelioration of the alpha-synuclein dependent phenotypes. The pre-clinical model will be periodically assessed for changes in motor performance, coordination and olfactory capacity. Finally, changes in alpha-synuclein aggregation/depositation will be assessed as alterations in proteinase K-resistant alpha-synuclein inclusions in the substantia nigra and olfactory bulb.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Clinical mutations in ATP13a2 result in Parkinsonism features while its over-expression suppresses alpha-synuclein’s toxicity in model systems, making it a strong potential target for PD therapeutic development. The successful amelioration of alpha-synuclein associated neurodegeneration in a pre-clinical model’s brain in this project could lead to the design of novel therapeutic strategies aiming at enhancing ATP13a2 activity.
Anticipated Outcome:
The successful demonstration that increased ATP13a2 expression reduces alpha-synuclein dependent defects characteristic of PD would validate ATP13a2 as a PD therapeutic target. Such amelioration by elevated ATP13a2 levels would encourage efforts to discover approaches to enhance the activity of the ATP13a2 enzyme. Alternatively, further research could identify the molecular mechanism by which ATP13a2 suppresses alpha-synuclein that would likely illuminate alternative approaches to enhance the ATP13a2 dependent suppression of alpha-synuclein.