Project Details
Projekt
warp’d: Integrating transcriptome and DNA methylome data to discern accelerated from delayed adaptations in the unfolding of Parkinson’s disease
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 470987719
In the still largely enigmatic etiology of Parkinson disease (PD), age arises as the strongest susceptibility factor, and molecular perturbations underlying the disease state share key characteristics with advanced age. Yet, aging is not PD as the prevalence of 1-2% even in individuals of 80+ years of age reflects.In fact, our results in rodent models of PD show an intriguing bimodality of perturbations that lead to the disease state: While there are indeed genes that change expression in an accelerated aging-like mode, a second class of genes is characterized by delay or failure to adapt appropriately over time resulting in expression trajectories to diverge from natural aging. We and others found evidence for divergences of age and PD in human, too. However, revealing a more complete understanding of longitudinal disease unfolding in human brain directly remains elusive.Hence, indirect readouts are required. We propose (i) to extend our preliminary results in rodent models that show disease-associated perturbations to be reflected in DNA methylation (DNAm) patterns, too. Then (ii) to integrate perturbation patterns in animal models with data from DNAm interrogations in patient brain, and (iii) to correlate these perturbation patterns in brain with existing—in part longitudinal—DNAm data in blood from large patient cohorts.Through the proposed laboratory and analytical work, we seek to reveal deviating DNAm trajectories in blood that can serve as proxy to infer disease-associated alterations in brain that may aid in arriving at a much-needed earlier diagnosis of PD.
DFG Programme
Research Grants
