Comparison of Nedd4 and GBA for Improving Protein Handling and Reducing Alpha-synucleinopathy
Target Validation, 2015
Study Rationale: † † † † † † † † ††
Lysosomes are key intra-cellular organelles involved in the degradation of proteins including alpha-synuclein. Lysosomal protein degradation systems fail in Parkinsonís 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.
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.
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 Parkinsonís 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.
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.
Assistant Professor of Psychiatry and Director, Neuroregeneration Institute at Harvard Medical School/McLean Hospital
Location: Belmont, Massachusetts, United States