Differentially Expressed miRNAs in Age-Related Neurodegenerative Diseases: A Meta-Analysis

Abstract

To date, no neurodegenerative diseases (NDDs) have cures, and the underlying mechanism of their pathogenesis is undetermined. As miRNAs extensively regulate all biological processes and are crucial regulators of healthy brain function, miRNAs differentially expressed in NDDs may provide insight into the factors that contribute to the emergence of protein inclusions and the propagation of deleterious cellular environments. A meta-analysis of miRNAs dysregulated in Alzheimer's disease, Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and frontotemporal lobar degeneration (TDP43 variant) was performed to determine if diseases within a proteinopathy have distinct or shared mechanisms of action leading to neuronal death, and if proteinopathies can be classified on the basis of their miRNA profiles. Our results identified both miRNAs distinct to the anatomy, disease type and pathology, and miRNAs consistently dysregulated within single proteinopathies and across neurodegeneration in general. Our results also highlight the necessity to minimize the variability between studies. These findings showcase the need for more transcriptomic research on infrequently occurring NDDs, and the need for the standardization of research techniques and platforms utilized across labs and diseases.

Keywords: amyloidopathies; miRNAs; neurodegenerative diseases; synucleinopathies; tauopathies.

Figure 1

The average number of differentially expressed miRNAs per profile in Parkinson’s disease, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, dementia with Lewy bodies, frontotemporal lobar degeneration and Alzheimer’s disease. A total of 17 ± 21, 11 ± 16, 8, 2, 3, 6 ± 1 and 17 ± 21 miRNAs were upregulated in PD, MSA, CBD, PSP, DLB FTLD and AD, respectively. A total of 16 ± 20, 25 ± 25, 4, 6 ± 6, 18, 10 ± 4 and 18 ± 27 miRNAs were downregulated in PD, MSA, CBD, PSP, DLB FTLD and AD, respectively. Data are represented as mean ± SD. N = 9, 8, 1, 2, 1, 2, 22 upregulated miRNA profiles, and 12, 7, 1, 2, 1, 2, 22 downregulated miRNA profiles in PD, MSA, CBD, PSP, DLB FTLD and AD, respectively. The SD observed is lowest in NDDs with fewer profiles considered.

Figure 2

Distribution of upregulated (red) (A) and downregulated (blue) (B) miRNAs. N = 45 (upregulated) and 47 (downregulated) expression profiles. The X-axis in each heatmap corresponds to a miRNA profile, while the Y-axis corresponds to individual miRNAs differentially expressed. The heatmap classifies profiles on the basis of miRNA differential expression in a specific disease, pathology or anatomy. The heatmap demonstrated minimal clustering as per these specified criteria. A greater number of upregulated miRNAs were repeatedly expressed. The distance between profiles was calculated using the asymmetric binary similarity measure.

Figure 3

Venn diagrams representing the overlap of miRNAs differentially expressed in individual neurodegenerative diseases, sharing a common underlying protein pathology. Overlap is displayed between amyloidopathies (A,B), ɑ-synucleinopathies (C,D), tauopathies (E,F) and TDP-43 proteinopathies (G,H). (A,C,E,G) demonstrate upregulated miRNAs, while (B,D,F,H) demonstrate downregulated miRNAs in the individual proteinopathies. A 0–1% overlap was observed between diseases included within a single proteinopathy.

Figure 4

Venn diagrams representing the overlap of miRNAs differentially expressed within a proteinopathy (A,B), and in a specific anatomical region or biofluid (C,D). (A,C) demonstrate upregulated miRNAs, while (B,D) demonstrate downregulated miRNAs. Few miRNAs were unique to each proteinopathy and anatomy. 15% and 5% of DE miRNAs were commonly down- and upregulated, respectively, between all protein pathologies. Less than 5% of DE miRNAs obtained from the expression profiles were commonly DE in both brain material and biofluids.

Figure 5

Venn diagrams representing miRNAs consistently differentially expressed post RRA analyses. The overlap between miRNAs from brain tissue and biofluids: upregulated (A), downregulated (B). Overlap of DE miRNAs between proteinopathies: upregulated (C), downregulated (D).