Mechanism and Modulation of Alpha-Synuclein Expression

Promising Outcomes of Original Grant:
In the initial grant, we tested the hypothesis that GATA-2 is a direct regulator of alpha-synuclein expression in dopaminergic neurons and therefore represents a novel pathway that can be targeted to modulate alpha-synuclein levels. We demonstrated that GATA-2-null embryonic stem cells retain the capacity to differentiate into neurons, including those that express a key marker of neurons relevant to Parkinson’s disease. The GATA-2-null cells exhibited reduced alpha-synuclein expression relative to neurons derived from wild-type embryonic stem cells, thus supporting our hypothesis.

Objectives for Supplemental Investigation: 
While GATA-2 induces alpha-synuclein expression, the extent to which it controls other important genes in dopaminergic neurons is completely unclear. We hypothesize that GATA-2 establishes a crucial genetic network, which includes alpha-synuclein as well as other genes that functionally interface with alpha-synuclein. In the supplemental work, we shall define the genetic network instigated by alpha-synuclein using genome-wide approaches.

Importance of This Research for the Development of a New PD Therapy: 
A logical strategy to treat Parkinson’s in certain contexts is to pharmacologically reduce the levels of alpha-synuclein. Our studies are aimed at establishing a transcriptional pathway that confers alpha-synuclein expression. This work will allow one to understand how alpha-synuclein expression is elevated in certain contexts and is expected to provide one or more completely new targets for the development of anti-Parkinson’s therapeutics.