Study Rationale:
A hallmark of Parkinson’s disease (PD) is aggregates of the protein alpha-synuclein. One of the main pathways to remove excess amounts of alpha-synuclein, which can be toxic for the cell, is chaperone-mediated autophagy (CMA). CMA identifies and transports proteins for degradation, essentially cleaning up the cell to keep it healthy. We have previously shown that if we induce CMA activity in brain cells in small disease models, we can reduce excess levels of alpha-synuclein and protect against the toxicity.
Hypothesis:
In this study, we seek to investigate whether induction of the activity of the CMA pathway may protect brain cells against alpha-synuclein-mediated toxicity in larger disease models.
Study Design:
We will induce CMA activity by expressing high levels of the lysosomal protein LAMP2A through a gene therapy approach. To recapitulate the pathological alpha-synuclein load present in PD patients, we will isolate aggregates from human post-mortem PD brains and implant them in the brain of these models. Comparing models where LAMP2A is upregulated and in control models (normal LAMP2A), we will measure alpha-synuclein protein levels, both within cells and in the extracellular space, as well as dopamine neuron survival.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
In the current study we aim to investigate whether induction of a cell pathway responsible for the clearance of unwanted proteins could protect monkey brain cells from dying. If this therapeutic strategy is proven successful, this may pave the way for its possible clinical utility in the treatment of PD.
Next Steps for Development:
If successful in our goals, in future studies we seek to assess whether boosting the CMA pathway could ameliorate or stabilize deposition of alpha-synuclein and dopaminergic dysfunction in model brain, in an attempt to mimic the human PD clinical setting, where such phenomena are already ongoing.