Project description:Therapeutic development for Huntington's disease (HD) would benefit from a method to monitor disease progression and treatment efficacy, ideally using blood biomarkers. Previously, HD-specific signatures were identified in human blood which adequately represented signatures in human brain, showing biomarker potential. Since drug candidates are normally first screened in rodent models, we aimed to identify HD-signatures in blood and brain of YAC128 HD mice and validate these with our previously identified human signatures. In both brain and blood, we identified HD-associated modules using Weighted Gene Co-expression Network Analysis (WGCNA) representing various biological processes previously associated with HD. Disease-related processes in blood and brain showed substantial overlap, including processes related to protein modification, cell cycle, RNA splicing, nuclear transport and vesicle-mediated transport. Moreover, the disease-associated processes shared between mouse blood and brain were highly comparable to those previously identified in human blood and brain. In addition to shared pathology, we identified HD-associated blood modules showing blood-specific pathology.
Project description:Parkinson’s disease (PD) progresses relentlessly and affects five million people worldwide. Laboratory tests for PD are critically needed for developing treatments designed to slow or prevent progression of the disease. We performed a transcriptome-wide scan in 105 individuals to interrogate the molecular processes perturbed in cellular blood of patients with early-stage PD. The molecular marker here identified is strongly associated with risk of PD in 66 samples of the training set (third tertile cross-validated odds ratio of 5.7 {P for trend 0.005}). It is further validated in 39 independent test samples (third tertile odds ratio of 5.1 {P for trend 0.04}). The genes differentially expressed in patients with PD, or Alzheimer’s or progressive supranuclear palsy offer unique insights into disease-linked processes detectable in peripheral blood. Combining gene expression scans in blood and linked clinical data will facilitate the rapid characterization of candidate biomarkers as demonstrated here with respect to PD. Keywords: disease state analysis
Project description:Rapid, simple and reliable blood tests for Parkinson’s disease (PD) may enable pre-symptomatic diagnosis and facilitate disease-changing treatments. Here, we report escalated elevated levels of angiogenin-cleaved a disease specific group of nuclear genome-originated tRNA fragments (hereafter, PD-tRFs) carrying a unique seven-nucleotide motif in substantia nigra, cerebrospinal fluid and blood of PD patients. A blood test using RNA isolated from whole blood and dual multiplexl qPCR primers for PD-tRFs and mitochondrial-originated tRFs (MT-tRFs) successfully distinguished pre-symptomatic PD patients from controls, outperforming traditional clinical scoring (ROC-AUC of 0.86 vs. 0.73). Indicating relevance to disease symptoms, PD patients carrying GBA, SNCA or LRRK2 mutations presented elevated blood PD/MT-tRF ratios compared to mutations-carrying non-symptomatic individuals which indicates relevance to disease symptoms. Furthermore, PD-tRFs’ potential for ribosomal association predicted translational inhibition. Intriguingly, PD-tRFs levels declined both in patients’ blood following deep brain stimulation andas well as in in depolarized neuroblastoma cells where PD-tRFs presented transientlydepolirization impaired impacted ribosomal associations. Our findings facilitate a sensitive and accurate blood test for early PD.
