Tau regulation by METTL14-mediated RNA m6A modification in Pick's disease

PROJECT SUMMARY/ABSTRACT Tauopathies are a group of neurodegenerative diseases that are histopathologically characterized by abnormal accumulation and aggregation of tau in human brains. In addition to dysregulation of tau post- translational modifications and other causes of tau protein pathogenicity, abnormal tau mRNA metabolism is believed to play an important role, although the underlying mechanism remains elusive. N6-methyladenosine (m6A) methylation of RNA is the most prevalent, abundant and conserved internal modification in eukaryotic RNAs and it influences fundamental aspects of RNA metabolism including degradation, translation, splicing, and nuclear export. While RNA m6A dysregulation is implicated in the neurodegenerative diseases, the potential role of RNA m6A dysregulation in Tau mRNA metabolism and tauopathy in neurodegeneration has never been investigated. Our group reported that neuronal m6A reduction contributes to neurodegeneration in Alzheimer’s Disease (AD) by affecting CCND2 mRNA stability and inducing abnormal cell cycle events. In our pilot study, we noted that Tau mRNA contains m6A modification sites. Importantly, we found decreased neuronal m6A levels along with significantly reduced expression of m6A methyltransferase METTL14 in brains from Pick’s Disease (PiD), a tauopathy-related neurodegenerative disease characterized by accumulation of 3-repeat (3R) tau isoforms in pick bodies. These results suggest that RNA m6A dysregulation may be involved in tauopathy. Along this line, we found conditional knockout (cKO) of METTL14 leads to m6A reduction, Tau mRNA hypo-methylation, and Tau accumulation in mouse brains. Based on these results, we hypothesize that METTL14 depletion-mediated RNA m6A reduction affects Tau mRNA metabolism that leads to changes in splicing and tau accumulation in tauopathy. We will determine the effect of METTL14 depletion-mediated m6A reduction on Tau mRNA metabolism by affecting its alternative splicing and stability in primary neurons and mouse brains. A new hTau KI mouse model will be used to test whether METTL14 cKO leads to abnormal tau mRNA metabolism and tau-related neurodegeneration. The successful completion of this study will provide novel mechanistic insights into tau mRNA metabolism and tauopathy. It offers a new therapeutic target of tau mRNA metabolism for tauopathy during tau-related neurodegeneration.