Objective/Rationale:
There is a clear heterogeneity in the susceptibility of dopamine neurons to Parkinson’s disease. Indeed, neurons of the substancia nigra ventral tier are specifically lost in Parkinson patients and pre-clinical models of the disease. While the evidence for dopamine diversity is definitive, it is unclear when this diversity is generated. Several gain and loss of function studies at the progenitor level have considered dopamine progenitors as a relatively uniform pool of cells. We challenge this dogma, and hypothesize that there is a developmental basis for dopamine neuron diversity.
Project Description:
We intend to use distinct gene expression patterns in dopamine neuron progenitors to unravel dopamine diversity and gain genetic access to the subset of neurons particularly susceptible in Parkinson’s disease. Our previous work led us to propose that the Lmx1a dopamine progenitor domain can be parceled into distinct sub-domains, each giving rise to distinct dopamine cohorts. We propose to use genetic inducible fate mapping to indelibly label a subpopulation of dopaminergic progenitors and determine their subsequent fate.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
A key motivation for detailing the developmental underpinnings of dopamine diversity is the exciting potential for stem cell derived models and therapeutics. To take this to the next level, it is critical to refine embryonic stem cell manipulations to specifically produce neurons that are prominently lost in Parkinson patients, and that are indeed specialized for function in the putamen. Thus, a clear grasp of the molecules that govern embryonic dopamine diversity is an inevitable step towards successful stem cell-derived therapeutics.
Anticipated Outcome:
We expect to genetically label a cohort situated mainly in the ventral tier of the substantia nigra, and to a lesser extent in other dopamine regions. Furthermore, successful completion of these experiments will provide an excellent tool for genetically manipulating a key dopamine subtype. This will enable isolation of these neurons for transcriptomic and proteomic analysis, as well as genetic manipulation of these neurons to study their connectivity and function. Detailing the properties of this dopamine subtype, specifically vulnerable in Parkinson’s disease, will undoubtedly result in greater understanding of the disease course and open new avenues for early diagnosis.