MicroRNAs Changes Precede Symptoms in Tauopathies

Tauopathies belong to a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles in the human brain.

MicroRNAs (miRNAs) and short interfering RNAs (siRNA) comprise a class of about 20 nucleotides-long RNA fragments that block gene expression by attaching to molecules of messenger RNA in a fashion that prevents them from transmitting the protein synthesizing instructions they had received from the DNA. MiRNAs resemble siRNAs of the RNA interference (RNAi) pathway, except miRNAs derive from regions of RNA transcripts that fold back on themselves to form short hairpins, whereas siRNAs derive from longer regions of double-stranded RNA. With their capacity to fine-tune protein expression via sequence-specific interactions, miRNAs help regulate cell maintenance and differentiation. Due to their stability in biological fluids, there is increasing interest in using microRNAs as biomarkers for disease prediction and diagnosis.

To determine whether microRNA alterations in tauopathy contributed to pathological conditions, investigators at Indiana University (Bloomington, USA) first determined which hippocampal miRs were altered at the presymptomatic and symptomatic stages of tauopathy using rTg4510 mice (Tau mice), a well-characterized tauopathy model.

In the second phase, miR-RNA pairing analysis was conducted to identify putative miR targets. Next, they overexpressed miR142, one of the miRs known to be upregulated in tauopathy, in the brains of wildtype mice to examine its impact on gene expression. Finally, they used bioinformatics analysis to reveal several overlapping gene transcriptional changes as well as canonical and disease-associated pathways between Tau and miR142 overexpression.

Results published in the June 18, 2018, online edition of the journal Nature Scientific Reports showed that RNAseq transcriptome studies had revealed several overlapping biological and disease associated pathways affected by either Tau or miR142 overexpression, including the Stat3 (signal transducer and activator of transcription 3) and Tnfr2 (tumor necrosis factor receptor 2) signaling pathways. Ultimately, changes in microRNA were detectable in mice long before they began showing symptoms from neurodegeneration.

"Identifying biomarkers early in a disease is important for diagnosing the condition, and following its progression and response to treatment," said senior author Dr. Hui-Chen Lu, professor of neuroscience at Indiana University. "You need something that can predict your future. Higher levels of pre-symptomatic microRNA dysregulation are significant because it strongly suggests that it may have a role in changes in the brain in later stages. The next step will be to learn whether microRNA 142 is easily detectable through a blood test, a key quality for a truly non-invasive biomarker."

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