Common signatures of differential microRNA expression in Parkinson's and Alzheimer's disease brains

Dobricic, V.; Schilling, M.; Farkas, I.; Gveric, D.; Schulz, J.; Middleton, L.; Gentleman, S.; Parkkinen, L.; Bertram, L.; Lill, C. M.

doi:10.1101/2022.01.31.478486

bioRxiv · 10.1101/2022.01.31.478486

Common signatures of differential microRNA expression in Parkinson's and Alzheimer's disease brains

Dobricic, V.·Schilling, M.·Farkas, I.·Gveric, D.·Schulz, J.·Middleton, L.·Gentleman, S.·Parkkinen, L.·Bertram, L.·Lill, C. M.

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Abstract

BackgroundDysregulation of microRNA (miRNA)-mediated gene expression has been implicated in the pathogenesis and course of many neurodegenerative diseases including Parkinsons disease (PD). However, the functionally relevant miRNAs remain largely unknown. Previous meta-analyses on differential miRNA expression data in post-mortem PD brains have highlighted several miRNAs showing consistent and statistically significant effects. However, these meta-analyses were based on exceedingly small sample sizes. MethodsIn this study, we quantified the expression of the four most compelling PD candidate miRNAs from these meta-analyses in the superior temporal gyrus (STG) of one of the largest case-control post-mortem brain datasets available (261 samples), thereby quadruplicating previously investigated sample sizes. Furthermore, we probed for common differential miRNA expression signatures with Alzheimers disease (AD) by also analyzing these miRNAs in post-mortem STG of 190 AD patients and controls and by testing six top AD miRNAs in the PD brains. ResultsOf all ten analyzed miRNAs, PD candidate miRNA homo sapiens (hsa-) miR-132-3p showed evidence for differential expression in both PD (p=4.89E-06) and AD (p=3.20E-24), and AD miRNAs hsa-miR-132-5p (p=4.52E-06) and hsa-miR-129-5p (p=0.0379) showed evidence for differential expression in PD. Combining these novel data with previously published data substantially improved the statistical support (=3.85E-03 using Bonferroni correction) of the corresponding meta-analyses clearly and compellingly implicating these miRNAs in both PD and AD. Furthermore, hsa-miR-132-3p/-5p (but not hsa-miR-129-5p) showed association with neuropathological Braak PD staging (p=3.51E-03/p=0.0117), suggesting that these miRNAs may play a role in -synuclein aggregation beyond the early disease phase. ConclusionsOur study represents the largest independent assessment of recently highlighted candidate brain miRNAs in PD and AD post-mortem brain samples, to date. Our results implicate hsa-miR-132-3p/-5p and hsa-miR-129-5p to be differentially expressed in both PD and AD brains, potentially pinpointing shared pathogenic mechanisms across these neurodegenerative diseases.

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Dobricic, V., Schilling, M., Farkas, I., Gveric, D., Schulz, J., Middleton, L., Gentleman, S., Parkkinen, L., Bertram, L., Lill, C. M.. 2022-01-31. Common signatures of differential microRNA expression in Parkinson's and Alzheimer's disease brains. https://doi.org/10.1101/2022.01.31.478486

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