This grant builds upon the research from a prior grant: Chaperone-mediated Autophagy to Counteract Alpha-synuclein Pathology
Study Rationale: One of the main pathways to remove excess amounts of the alpha-synuclein protein that is linked to Parkinson’s disease (PD) is the lysosomal chaperone-mediated autophagy (CMA) pathway. Our original MJFF-funded project investigated whether inducing CMA could benefit a preclinical, non-human primate synucleinopathy model by targeting the pathway’s LAMP2A receptor. Our data show that overexpressing LAMP2A protects dopamine neurons from neurodegeneration induced by inoculation of PD brain extracts. Animals injected with LAMP2A displayed significantly improved performance in behavioral tests related to cognitive function. In addition, LAMP2A overexpression seemed to decrease the amount of alpha-synuclein found in the animals’ fluid samples.
Hypothesis: We hypothesize that inducing the CMA lysosomal clearance pathway through overexpression of the LAMP2A receptor facilitates removal of pathological forms of alpha-synuclein from the brain and biological fluids in a preclinical synucleinopathy model in which PD extracts are inoculated.
Study Design: In our continuation of this project, we will conduct a thorough longitudinal assessment of pathological alpha-synuclein protein load in the brain and biological fluid samples we have collected. We have selected three state-of-the-art assays in an attempt to measure the effects of our gene therapy approach in reducing proteopathic seed load. In parallel, we will also map the extent of alpha-synuclein spreading in areas beyond the injection sites, focusing on the corresponding cortical areas to explain the beneficial cognitive effects.
Impact on Diagnosis/Treatment of Parkinson’s disease: If our gene therapy approach leads to alpha-synuclein clearance and mitigation of its effects on motor and cognitive function in a primate model, this project could pave the way for application in people with PD; alternatively, pharmacological strategies for stimulating this clearance pathway could be attempted.
Next Steps for Development: In future studies, we will assess whether our approach can remove or stabilize pre-established alpha-synuclein aggregates and thereby diminish the dopamine loss and cognitive dysfunction in the brains of non-human primates — a condition that would mimic the clinical presentation of PD, where such phenomena are already ongoing.