A rapidly developing and fatal neurodegenerative disorder, MSA is frequently misdiagnosed or undetected until later stages due to its systemic nature, undefined etiopathogenesis, and multifaceted clinical presentation. In an attempt to unravel molecular changes in MSA, scientists from UC San Diego performed analysis of microRNA (miRNA) and messenger RNA (mRNA) expression in postmortem striatal tissue from patients with the Parkinsonian variant of MSA and aged-matched healthy controls.
Advances in nucleotide sequencing technologies and computational tools have provided researchers with an unprecedented opportunity to probe novel diagnostic and prognostic markers and therapeutic targets. In a recent study conducted by Kim et al. (2019)1, a systematic interrogation of both coding and non-coding elements of the human genome helped uncover regulatory circuits that underlie neurodegeneration in multiple system atrophy (MSA). Their findings shed light on the efficacy of interactome-based approaches in elucidating the relationship between perturbed molecular mechanisms and disease manifestation.
800 miRNAs were comprehensively profiled with the nCounter® Human v3 miRNA assay to reveal global changes in the epigenetic landscape of MSA. 59 miRNAs exhibited altered levels in MSA (two-tailed T-test; p-value < 0.01). Top miRNA hits were functionally linked to key pathological signaling cascades that include extracellular matrix interactions, prion disorders, autophagy, and inflammation. A targeted evaluation of the expression profile of 770 neurodegeneration-associated genes was carried out in parallel using the nCounter® Neuropathology panel. 96 genes were differentially expressed in MSA (two-tailed T-test; p-value < 0.01), with the majority involved in inflammation, myelination, and autophagy.
Results from both analyses were then integrated to uncover the miRNA-mediated regulation of gene expression. Links between 24 miRNAs and 38 mRNA target genes were identified using miRNA target filtering in Ingenuity Pathway Analysis (IPA) with Pearson’s correlation of abundance (p-value < 0.05). Magia and TargetScan were then performed to incorporate interactions involving relevant transcription factor nodes and regulatory molecules. The expanded miRNA-mRNA target gene-transcription factor network exhibited enrichment for striatum-associated functions, most notably neuroinflammation.
The authors also noted a significant overlap in pathology between MSA and Alzheimer’s disease (AD). Differentially expressed genes specifically deregulated in MSA were enriched for AD and amyloidosis. At the network level, transcriptional alteration was also observed in miRNA target genes that encode amyloid processing proteins.
In agreement with previous reports, miRNA deregulation in MSA appears to correlate with the altered expression of neuropathology genes. By performing targeted gene expression profiling, the authors were able to contextualize findings from their global analysis of the miRNA and underscore disease-specific molecular targets. They generated a comprehensive miRNA-target gene-transcription factor regulatory network to further decode the complex molecular machinery of MSA. They also used multiple layers of information to highlight miRNA’s involvement in neurodegenerative processes such as neuroinflammation, disrupted myelination, and α-Synuclein accumulation due to defective autophagy and prion mechanisms. As such, they were able to represent miRNAs as promising ante-mortem and clinically actionable biomarkers for MSA and other neurodegenerative diseases.
1. Kim, T., Valera, E. & Desplats, P. Alterations in Striatal microRNA-mRNA Networks Contribute to Neuroinflammation in Multiple System Atrophy. Mol. Neurobiol. (2019). doi:10.1007/s12035-019-1577-3
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