For Researchers > Basic/Pre-Clinical Research > Parkinson's Disease > Generating A Population of Pure Dopamine Neurons

A central goal in neurobiology has been the discovery of ways in which to rescue dopamine (DA) neurons from the progressive degeneration that occurs during aging or in Parkinson's disease and to replace lost tissue with transplanted cells capable of DAergic function. These strategies depend for their success on a reliable source of transplantable DA neurons and the identification of factors relevant to their growth and survival. Unfortunately, progress on both of these fronts has been greatly impeded by the fact that DA neurons comprise less than 1 percent of the total cells currently found in mesencephalic cultures and in transplants. Discovering ways in which to segregate DA neurons from other cell types poses a significant challenge, but a necessary next step.

One focus of the laboratory is the discovery of ways to specifically tag and isolate pure populations of DA neurons from the brain or from stem/progenitor cells that have been persuaded to behave as DA neurons, i.e., express the DA biosynthetic enzyme tyrosine hydroxylase (TH). These studies suggest that it is possible to isolate highly enriched populations of DA neurons after sorting fluorescent midbrain cells derived from transgenic mice bearing a highly expressed 11.0 kb human TH construct that drives expression of a green fluorescent protein (GFP), as well as from stem/ progenitor cells that have been coaxed into expressing TH and the lentivirally delivered hTH-GFP tag.

Using these models and multidisciplinary analytical methods, which incorporate molecular, anatomical, biochemical and behavioral assessments, our current goals are to determine: 1) the conditions that yield the most homogeneous population of transgenic or stem/progenitor cells exhibiting DA properties; 2) the culture conditions that are required for the survival, growth and preservation of a DA phenotype in these cells; 3) the growth conditions that are required for their successful transplantation into animal models of Parkinson's disease. Knowledge gleaned from these studies will hopefully provide the building blocks needed to devise new cell replacement strategies for the treatment of Parkinson's disease.

Related publications:

Suon S, Jin H, Donaldson AE, Caterson EJ, Tuan RS, Deschennes G, Marshall C, and Iacovitti L . Adult human bone marrow stem cells transiently differentiate in culture to express CNS proteins. Stem Cells 2004. Submitted.

Yang M, Donaldson AE, Marshall CE, Shen J, Iacovitti L . Studies on the differentiation of dopaminergic traits in human neural progenitor cells in vitro and in vivo . Cell Transplantation 2004. In Press.

Yang M, Donaldson AE, Jiang Y, Iacovitti L. Factors influencing the differentiation of dopaminergic traits in transplanted neural stem cells. Mol Cell Neurobiol 2003 Oct;23(4-5):851-64.

Yang M, Stull ND, Snyder EY, Berk MA, Iacovitti L . Neuronal stem cells spontaneously differentiate into dopaminergic neurons after transplantation into the intact or 6-hydroxydopamine lesioned rate. Exp Neurol 2002;177:50-60.

Stull ND, Jung JW, Iacovitti L . Induction of a dopaminergic phenotype in cultured striatal neurons by bone morphogenetic proteins. B rain Res Dev Brain Res . 2001 Sep 23;130(1):91-8.