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Updated: Feb 11, 2026
Use of Alu Element Containing Minigenes to Analyze Circular RNAs
Published on: March 10, 2020
The human MAPT locus generates circular RNAs
Justin R Welden1, Jacob van Doorn1, Peter T Nelson1
1University of Kentucky, Lexington, KY 40503, United States.
Abstract:
The microtubule-associated protein Tau, generated by the MAPT gene is involved in dozens of neurodegenerative conditions ("tauopathies"), including Alzheimer's disease (AD) and frontotemporal lobar degeneration/frontotemporal dementia (FTLD/FTD). The pre-mRNA of MAPT is well studied and its aberrant pre-mRNA splicing is associated with frontotemporal dementia. Using a PCR screen of RNA from human brain tissues, we found that the MAPT locus generates circular RNAs through a backsplicing mechanism from exon 12 to either exon 10 or 7. MAPT circular RNAs are localized in the cytosol and contain open reading frames encoding Tau protein fragments. The MAPT exon 10 is alternatively spliced and proteins involved in its regulation, such as CLK2, SRSF7/9G8, PP1 (protein phosphatase 1) and NIPP1 (nuclear inhibitor of PP1) reduce the abundance of the circular MAPT exon 12 → 10 backsplice RNA after being transfected into cultured HEK293 cells. In summary, we report the identification of new bona fide human brain RNAs produced from the MAPT locus. These may be a component of normal human brain Tau regulation and, since the circular RNAs could generate high molecular weight proteins with multiple microtubule binding sites, they could contribute to taupathies.
Insights
Researchers discovered novel circular RNAs from the MAPT gene in human brains. These circular RNAs may regulate Tau protein and contribute to tauopathies like Alzheimer's disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The microtubule-associated protein Tau (MAPT) is implicated in neurodegenerative tauopathies, including Alzheimer's disease (AD) and frontotemporal dementia (FTD).
- Aberrant pre-mRNA splicing of the MAPT gene is linked to FTD, highlighting the importance of MAPT RNA regulation.
Purpose of the Study:
- To identify novel RNA species generated from the MAPT locus in human brain tissue.
- To investigate the potential role of these novel RNAs in Tau regulation and tauopathies.
Main Methods:
- Utilized PCR screening of RNA from human brain tissues to detect circular RNAs.
- Employed transfection of HEK293 cells to study the regulation of MAPT circular RNAs by specific proteins.
Main Results:
- Identified bona fide circular RNAs produced from the MAPT locus via backsplicing (exon 12 to exon 10 or 7).
- These MAPT circular RNAs are cytosolic and contain open reading frames encoding Tau protein fragments.
- Regulatory proteins (CLK2, SRSF7/9G8, PP1, NIPP1) were found to reduce the abundance of MAPT exon 12→10 backsplice RNA.
Conclusions:
- Reported the identification of new MAPT circular RNAs in the human brain.
- These circular RNAs may be involved in normal Tau regulation.
- The potential to encode Tau fragments with multiple microtubule-binding sites suggests a role in the pathogenesis of tauopathies.
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