Objective: To investigate the molecular correlates of clinical heterogeneity in Parkinson’s disease (PD) in the striatum and peripheral blood.

Background: The molecular basis for clinical heterogeneity in PD is poorly understood. Moreover, the ability to use blood as a tool to distinguish the variable clinical outcomes in PD would be of enormous value.

Method: We performed RNA-sequencing on post-mortem striatum (caudate and putamen) from non-PD controls (n=40) and PD (n=35). For blood RNA-seq from Parkinson’s disease progression markers initiative (PPMI), we performed differential gene expression analysis in patients diagnosed with PD (n=479) and controls (n=195). Changes in gene expression with log₂ fold change ≥ 0.1 and q-value < 0.05 in PD compared to controls were considered significant.

Results: In both PD caudate and putamen there were increased levels of RNAs encoding proteins involved in regulation of  immune response and decreased levels of RNAs encoding proteins involved in mitochondrial dynamics and postsynaptic signaling. Additionally, we identified distinguishing molecular characteristics in each region that vary with development of cognitive impairment, motor complications, age at onset of disease, and disease duration. Cognitive impairment was associated with significant upregulation of stress response pathways specifically in the caudate but not putamen, while motor complications of PD were associated with endothelial pathways in the putamen. Later-onset PD was distinct from earlier-onset PD. Top pathways that distinguished PD blood from control subjects were related to neuronal functions, and  molecular features in the striatum associated with PD, cognitive impairment and  age of onset of disease were also evident in blood samples from PD subjects, thus providing independent validation of our observations in the brain, and establishing the relevance of blood transcriptome patterns in PD.

Conclusion: Together, these findings identify key molecular aberrations in the striatum in PD associated with the heterogeneous clinical features in PD and offer a roadmap  for focused future mechanistic and therapeutic studies. Importantly, the detection of concordant RNA patterns in brain and blood can be leveraged to develop molecular tools to predict clinical course and monitor responses to therapeutic interventions in a minimally invasive manner.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/concordant-rna-patterns-in-parkinsons-disease-brain-and-peripheral-blood/