The drastic motor deficit in Parkinson's disease (PD) patients is largely caused by a substantial loss of midbrain dopamine neurons (mDA). Careful morphometric studies have revealed a selective susceptibility of certain mDA populations. Thus, mDA neurons found in the ventral tier of the substantia nigra pars compacta (SNpc;A9) are more vulnerable, compared to mDA located in the dorsal tier of the SNpc, or in the Ventral Tegmental Area (A10). This differential susceptibility highlights the diversity of mDA populations. We hypothesize that in the developing midbrain, there are multiple distinct mDA progenitor pools, each of which gives rise to distinct mDA subtypes. We will attempt to determine the progenitor pool for the most susceptible type of dopamine neuron in PD. Accordingly, we will lineage trace one proposed mDA progenitor pool and determine whether its descendents populate the most vulnerable regions of the dopaminergic field i.e. the ventral tier of the SNpc. Next we will develop topographic maps for this DA subtype. Together, these experiments will provide a first glimpse into how mDA diversity is generated. Elucidating the developmental basis for this diversity will be critical for understanding differential susceptibility of mDA, as well as generating accurate ES or iPSC stem cell derived models and therapies for PD.

Public Health Relevance

In Parkinson's disease, a select subset of dopamine neurons is prone to degeneration. We aim to demonstrate that this is because dopamine neurons are inherently different from the time of their birth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS072703-02
Application #
8472547
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sutherland, Margaret L
Project Start
2012-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$186,366
Indirect Cost
$65,741
Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Poulin, Jean-Francois; Zou, Jian; Drouin-Ouellet, Janelle et al. (2014) Defining midbrain dopaminergic neuron diversity by single-cell gene expression profiling. Cell Rep 9:930-43