Alpha-synuclein in PD: pathogenesis and treatment
Abstract
The discovery that mutations in the gene for alphasynuclein could cause Parkinson's disease(PD) was the first demonstration that PD can have a genetic etiology. Since this initial discovery it has become apparent that alphasynuclein may also be a central feature in the pathogenesis of PD. We have recently demonstrated that alphasynuclein is central to early pathogenic events within the nigra of PD as only nigral neurons that display alphasynuclein positive aggregates display decreases in the dopaminergic markers tyrosine hydroxylase and Nurr1. Adjacent nigral PD neurons without aggregates display normal levels of these markers. Additionally, we have found that monkeys and humans have age-related increases in cytoplasmic alphasynuclein in nigral neurons as leading to our hypothesis that preventing age-related upregulation of alphasynuclein, rather than attempting to disaggregate already aggregated alphasynuclein might be a simpler therapeutic target. Based upon this line of thought, we propose in this application to determine to following: We will use single cell gene arrays to test the hypothesis that the molecular signature of cells under attack in PD (those expressing alphasynuclein aggregates) is different than those that normal (those without alphasynuclein aggregates). We will also test the hypothesis that early onset PD engendered via viral delivery of alpha synuclein to young monkeys will display a slower course of progression, more drug-induced complications, and attenuated nigrostriatal dysfunction relative to late onset PD engendered via viral vector administration of alpha synuclein to aged monkeys. Finally, we will test the hypothesis that decreasing cytoplasmic expression of alpha synuclein using siRNA directed against alphasynuclein will the increase phenotypic dopaminergic markers in an aged monkey model of PD. Taken together, these studies will aid in our understanding of the role of alphasynuclein and other gene markers in the pathogenesis of PD,
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2010
- Accession Number
- AD1001760
Entities
People
- Jeffrey H. Kordower
Organizations
- Rush University Medical Center