Impact of m6A RNA modifications in Alzheimer's disease and tauopathies

SUMMARY RNA modifications are altered in Alzheimer's Disease (AD) and related dementias. In particular, the post- transcriptional N6-methyladenosine modification of RNA (m6A-RNA) is dramatically dysregulated in human AD brains and in mouse and cell models of AD, and correlates with tau pathology. Tau physically interacts with m6A- RNA via the m6A-RNA binding protein hnRNPA2B1, and this interaction is increased in AD. However, we lack an understanding of the specific RNA sites that are differentially m6A-modified in AD and tauopathies, and of the downstream functional consequences and underlying mechanisms. In preliminary results, the Kampmann lab has uncovered new causal connections between tau, m6A-RNA, and hnRNPA2B1. In a genome-wide screen in human iPSC-derived neurons, knockdown of the m6A writers METTL3/METTL14 were among the strongest hits lowering tau aggregation. iPSC-derived neurons with the tauopathy-causing MAPT V337M mutation display increased m6A-RNA and altered levels and phosphorylation of many RBPs, including hnRNPA2B1. Intriguingly, we also observed mRNA mislocalization and misprocessing in MAPT V337M iPSC-derived neurons. Given that m6A and hnRNPA2B1 have been implicated in RNA trafficking and processing in neurons, we hypothesize that changes in m6A disrupt mRNA processing, trafficking and translation in AD/tauopathies, compromising neuronal function and survival. The Yeo lab has recently developed several innovative technologies that will enable us, for the first time, to simultaneously characterize RNA modifications and their downstream consequences in post- mortem brain tissue and model systems at scale and with unprecedented sensitivity. We will leverage our innovative methodologies to uncover m6A-RNA changes and their functional consequences in post-mortem brain tissue from subjects with AD and other tauopathies with unprecedented resolution, and to dissect the underlying causal mechanisms in human iPSC-derived neurons and mouse models of tauopathies. Thereby, it will advance our understanding of disease mechanisms and pinpoint potential novel therapeutic strategies.