Transcription Factors as Key Targets to Regulate The Selective Vulnerability of Dopamine Neurons

Study Rationale:                   
Why specific subsets of brain cells such as those containing the chemical messenger dopamine are particularly vulnerable and degenerate is one of the central unresolved mysteries in Parkinson's disease. Our recent work suggests that the most vulnerable brain cells have, as a common characteristic, a high level of energy expenditure and a particularly elaborate set of connections with target cells in brain circuits. Such special characteristics of dopamine-containing neurons depend on a set of key transcription factors, which are proteins that control the expression of key genes. Our recent work further shows that the transcription factors Lmx1a/b play key roles in the survival of adult dopamine-containing neurons and in the maintenance of their axon structures.

Hypothesis:
We hypothesize that overexpression of Lmx1a/b in vulnerable dopamine-containing neurons will protect these neurons and their connectivity with target cells.

Study Design:
We will use viral vectors to overexpress Lmx1a and/or Lmx1b in adult dopamine-containing neurons and determine whether this will be neuroprotective in two pre-clinical models of Parkinson’s disease. Four endpoints will be measured: the number of surviving dopamine-containing neurons, the density of their connections with target cells, the amount of dopamine release and motor behaviors.

Impact on Diagnosis/Treatment of Parkinson’s Disease:             
This project will represent a proof of principle that transcription factors or some the pathways they control could represent novel treatment strategies to protect dopamine-containing neurons against Parkinson’s disease.

Next Steps for Development:
If this project is successful, we will perform a series of follow-up experiments in a larger model of Parkinson’s disease to further validate the therapeutic potential of this strategy. We will also attempt to identify downstream effectors of these transcription factors in an effort to identify drugable targets that can be screened to identify new lead therapeutic agents.