Probing Nurr1 Expression in Parkinsonís Disease
Research Grant, 2014
Impaired function of the hormone receptor Nurr1 might contribute to the pathogenesis of Parkinsonís disease (PD) and is an active target for novel therapeutics. Previous studies suggest that Nurr1 microRNA levels may be reduced in lymphocytes of Parkinsonís patients.†
Here we will evaluate the expression of Nurr1 and select target genes in blood cells for associations with on a precise, digital expression platform. This case-control study will comprise 625 cases and 625 controls and will be nested in the Harvard Biomarker Study ó leveraging our established biobank and patient population.†
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
We will confirm (or refute) associations between expression of the PD-linked Nurr1 as well as Nurr1-responsive genes and early-stage PD ó an important step towards translating genetic and transcriptional clues into a biomarker potentially useful as companion diagnostic for Nurr1-directed therapeutics.
This investigation will help to clarify the utility of Nurr1 and Nurr1-responsive genes as potential markers for therapeutics development in PD.
Nurr1 (NR4A2) is a nuclear hormone receptor implicated in the growth, maintenance, and survival of dopaminergic neurons and a target for novel therapeutics in Parkinsonís disease (PD). Nurr1 trans-activates target genes involved in dopamine metabolism and mitochondrial function.
We analyzed the expression of the Nurr1 gene family and related nuclear hormone receptors as well as select target genes in a case-control study of 625 cases and 625 healthy controls nested within the Harvard Biomarkers Study population using digital transcript counting with molecular barcodes. 200 neurodegenerative disease controls were also included to estimate disease-specificity and -sensitivity.
Counts of a small set of candidate transcripts including a nuclear hormone receptor were statistically significantly increased in blood of patients with PD compared to both healthy and disease controls adjusting for demographic and hematological covariates. The expression of most other nuclear hormone receptor family members assayed was unchanged. This study helps to clarify the landscape of transcriptional markers robustly and reproducibly associated with early-stage PD in accessible human peripheral blood. It identified a small set of transcriptional markers potentially useful for clinical development.
Head of the Neurogenomics Lab and the Parkinson Personalized Medicine Initiative at Harvard and Brigham and Womenís Hospital
Associate Professor of Neurology at Harvard Medical School
Location: Cambridge, Massachusetts, United States