Funded Studies
Study Rationale:
Lysosomes are key intra-cellular organelles involved in the degradation of proteins including alpha-synuclein. Lysosomal protein degradation systems fail in Parkinson’s disease (PD). Nedd4 and glucocerebrosidase (GBA) are two important targets involved in the clearance of alpha-synuclein through lysosomal pathways. We have previously shown that overexpression of Nedd4 and GBA in the brain in models of abnormal alpha-synuclein aggregation (alpha-synucleinopathy) can reduce the buildup of alpha-synuclein characteristic of PD, and prevent dopamine neurons from dying. We do not know whether either target (Nedd4 or GBA) is therapeutically more efficacious than the other and/or whether simultaneous activation of Nedd4 and GBA will provide additive therapeutic effects.
Hypothesis:
We will determine whether using either Nedd4 or GBA pathway activation, or a combination of both targets, is more effective in reducing intra-cellular alpha-synuclein and protecting dopamine neurons from degeneration in models.
Study Design:
We will overexpress Nedd4 or GBA in neurons of (1) models that overexpress wildtype alpha-synuclein, or (2) models that express mutant alpha-synuclein specifically in dopaminergic neurons. We will measure activation of the Nedd4 and GBA protein degradation pathways and alpha-synuclein handling, and determine whether Nedd4 and GBA can act synergistically to protect vulnerable neurons from alpha-synuclein pathology and degeneration, or whether either Nedd4 or GBA delivery alone is more therapeutically effective.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Increasing Nedd4 and GBA activity by gene therapy or small molecules may be neuroprotective in PD and related alpha-synucleinopathies.
Next Steps for Development:
The success of this project will provide guidance on the development of therapeutics that activate Nedd4 and/or GBA pathways for reducing intracellular alpha-synuclein and protecting vulnerable neurons from degeneration in PD.
Additional Support:
This project was selected for a Stern Discovery Award with support from the former Michael Stern Parkinson's Research Foundation, which merged with The Michael J. Fox Foundation in 2015.