Funded Studies
Study Rationale:
Parkinson’s disease (PD) is a prevalent neurodegenerative movement disorder. Several genetic mutations that cause PD have been identified in patients. One such mutation targets auxilin, a protein which helps recycle synaptic vesicles (SVs) which facilitate neurotransmission, through which neurons communicate. The mutation disrupts the normal function of auxilin, but we do not know exactly how this results in PD. We are using a pre-clinical model with no auxilin function, neurons derived from stem cells of a patient and gene editing technology to understand how an auxilin mutation might cause PD.
Hypothesis:
Dopaminergic neurons and its neurotransmitter dopamine are the primary system affected in PD. Our experiments show that dopamine is not properly transported to SVs for neurotransmission, in our pre-clinical model. Based on this finding, we hypothesize that defects in the SVs and transporters which control dopamine movement leads to alteration in dopamine compartmentalization, which is already known to be toxic. This might ultimately cause PD in people with auxilin mutations.
Study Design:
1. We will monitor dopamine accumulation in the brains of pre-clinical models. We will also perform electron microscopy to evaluate localization of SV proteins and dopamine transporters. We will then grow dopaminergic neurons from pre-clinical models and study SVs and dopamine transporters.
2. Auxilin-linked stem cells from people with PD will be grown in a dish and reprogrammed to become dopaminergic neurons. We will then monitor dopamine accumulation and molecular signatures of PD in these neurons. We will experimentally increase the cellular amounts of auxilin and determine if increased levels save neurons from degeneration. We will also evaluate if this approach is beneficial to neurons having other PD mutations.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Understanding the biological mechanisms of PD associated with auxilin should lead to the development of treatments for people with PD who have auxilin mutations. Our study will also provide insights on whether auxilin can be a therapeutic target for other forms of PD.
Next Steps for Development:
If successful, this work might lead to drug discovery projects in research institutes and pharmaceutical companies to identify drugs that can increase auxilin, providing relief to people with Parkinson’s.