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

Dobricic, Valerija, Schilling, Marcel, Farkas, Ildiko, Gveric, Djordje O, Ohlei, Olena, Schulz, Jessica, Middleton, Lefkos, Gentleman, Steve M, Parkkinen, Laura, Bertram, Lars, Lill, Christina M·2022·Brain Communications
DOI 10.1093/braincomms/fcac274PMC PMC9645562

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Abstract

Dysregulation of microRNA gene expression has been implicated in many neurodegenerative diseases, including Parkinson’s disease. However, the individual dysregulated microRNAs remain largely unknown. Previous meta-analyses have highlighted several microRNAs being differentially expressed in post-mortem Parkinson’s disease and Alzheimer's disease brains versus controls, but they were based on small sample sizes. In this study, we quantified the expression of the most compelling Parkinson’s and Alzheimer’s disease microRNAs from these meta-analyses (‘candidate miRNAs’) in one of the largest Parkinson’s/Alzheimer’s disease case–control post-mortem brain collections available (n = 451), thereby quadruplicating previously investigated sample sizes. Parkinson’s disease candidate microRNA hsa-miR-132-3p was differentially expressed in our Parkinson’s (P = 4.89E−06) and Alzheimer’s disease samples (P = 3.20E−24) compared with controls. Alzheimer’s disease candidate microRNAs hsa-miR-132-5p (P = 4.52E−06) and hsa-miR-129-5p (P = 0.0379) were differentially expressed in our Parkinson’s disease samples. Combining these novel data with previously published data substantially improved the statistical support (α = 3.85E−03) of the corresponding meta-analyses, clearly implicating these microRNAs in both Parkinson’s and Alzheimer’s disease. Furthermore, hsa-miR-132-3p/-5p (but not hsa-miR-129-5p) showed association with α-synuclein neuropathological Braak staging (P = 3.51E−03/P = 0.0117), suggesting that hsa-miR-132-3p/-5p play a role in α-synuclein aggregation beyond the early disease phase. Our study represents the largest independent assessment of recently highlighted candidate microRNAs in Parkinson’s and Alzheimer’s disease brains, to date. Our results implicate hsa-miR-132-3p/-5p and hsa-miR-129-5p to be differentially expressed in both Parkinson’s and Alzheimer’s disease, pinpointing shared pathogenic mechanisms across these neurodegenerative diseases. Intriguingly, based on publicly available high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation data, hsa-miR-132 may interact with SNCA messenger RNA in the human brain, possibly pinpointing novel therapeutic approaches in fighting Parkinson’s disease.

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Graphical Abstract CC BY · PubMed Central
Figure 1 Overview of the study design. PD, Parkinson’s disease; AD, Alzheimer’s disease.
Figure 1 Overview of the study design. PD, Parkinson’s disease; AD, Alzheimer’s disease.CC BY · PubMed Central
Figure 2 Expression of candidate miRNAs in brain samples of Parkinson’s disease and Alzheimer’s disease patients versus controls and dependent on the neuropathological α-synuclein and tau Braak staging. This box and whisker plots display the relative quantity of Parkinson’s disease candidate miRNAs in post-mortem brain samples of the STG of 214 Parkinson’s disease patients versus 47 controls (A), the relative quantity of Parkinson’s disease candidate miRNAs in post-mortem brain samples of 99 Alzheimer’s disease patients versus 91 controls (B), and the relative quantity of Alzheimer’s disease candidate miRNAs in post-mortem brain samples of the STG of 214 Parkinson’s disease patients versus 47 controls (C). Differential gene expression was analysed using a GLM adjusting for RIN, age at death, PMIs and sex. The relative quantity of miRNA expression was calculated using the ΔΔCt method; diamonds represent the mean expression (cases relative to controls) based on the ΔΔCt method (relativequantity=2^(−(dCtcases–dCtcontrols))). Horizontal lines represent median values of the corresponding sample-specific values (individual dCt values normalized to the mean of the control samples), boxes represent IQRs and whiskers extend to the maximum observed value within 1.5 × the IQR; values outside this range but below the dashed line are depicted as dots. Outliers exceeding the dashed line are not shown (for scaling purposes) but counted and indicated by the numbers in the triangles. The box notches indicate the corresponding 95% confidence intervals (CIs). *Nominally statistically significant difference (α = 0.05). (D) This plot displays the gene expression of hsa-miR-132-3p and hsa-miR-132-5p normalized to endogenous control assay (dCt) dependent on α-synuclein and tau Braak staging in post-mortem brain samples of 213 Parkinson’s disease patients utilizing a GLM adjusting for RIN, age at death, PMIs and sex. Horizontal lines indicate the mean of the group.
Figure 2 Expression of candidate miRNAs in brain samples of Parkinson’s disease and Alzheimer’s disease patients versus controls and dependent on the neuropathological α-synuclein and tau Braak staging. This box and whisker plots display the relative quantity of Parkinson’s disease candidate miRNAs in post-mortem brain samples of the STG of 214 Parkinson’s disease patients versus 47 controls (A), the relative quantity of Parkinson’s disease candidate miRNAs in post-mortem brain samples of 99 Alzheimer’s disease patients versus 91 controls (B), and the relative quantity of Alzheimer’s disease candidate miRNAs in post-mortem brain samples of the STG of 214 Parkinson’s disease patients versus 47 controls (C). Differential gene expression was analysed using a GLM adjusting for RIN, age at death, PMIs and sex. The relative quantity of miRNA expression was calculated using the ΔΔCt method; diamonds represent the mean expression (cases relative to controls) based on the ΔΔCt method (relativequantity=2^(−(dCtcases–dCtcontrols))). Horizontal lines represent median values of the corresponding sample-specific values (individual dCt values normalized to the mean of the control samples), boxes represent IQRs and whiskers extend to the maximum observed value within 1.5 × the IQR; values outside this range but below the dashed line are depicted as dots. Outliers exceeding the dashed line are not shown (for scaling purposes) but counted and indicated by the numbers in the triangles. The box notches indicate the corresponding 95% confidence intervals (CIs). *Nominally statistically significant difference (α = 0.05). (D) This plot displays the gene expression of hsa-miR-132-3p and hsa-miR-132-5p normalized to endogenous control assay (dCt) dependent on α-synuclein and tau Braak staging in post-mortem brain samples of 213 Parkinson’s disease patients utilizing a GLM adjusting for RIN, age at death, PMIs and sex. Horizontal lines indicate the mean of the group.CC BY · PubMed Central

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Citations

Cites

Research works printed but not linked: 26

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Metadata

Authors
Dobricic, V., Schilling, M., Farkas, I., Gveric, D. O., Ohlei, O., Schulz, J., Middleton, L., Gentleman, S. M., Parkkinen, L., Bertram, L., & Lill, C. M.
Affiliations
  • Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck , 23562 Lübeck , Germany
  • Multiple Sclerosis and Parkinson’s Tissue Bank, Imperial College London , London W12 0NN , UK
  • Ageing and Epidemiology Unit (AGE), School of Public Health, Imperial College London , London W6 8RF , UK
  • Department of Brain Sciences, Hammersmith Hospital campus, Imperial College London , London W12 0HS , UK
  • Nuffield Department of Clinical Neurosciences, Oxford Parkinson’s Disease Centre, University of Oxford , Oxford OX3 9DU , UK
ORCID
Bertram, Lars
Venue
Brain Communications
Publisher
Oxford University Press (OUP)
Published
2022-10-28
Volume
4
Issue
6
ISSN
2632-1297
DOI
10.1093/braincomms/fcac274
PMC
PMC9645562
Cited by
22
References
5
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Deutsche Forschungsgemeinschaft (#391523883)
  • Cure Alzheimer’s Fund
  • Brain Bank
  • Imperial College London
  • Parkinson’s UK (258197, SC037554)
  • The Oxford Brain Bank
  • Medical Research Council
  • Brains for Dementia Research
  • Alzheimer Society and Alzheimer Research UK
  • NIHR Oxford Biomedical Research Centre
  • Michael J. Fox Foundation

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