Presenter of 1 Presentation
METHYLATED RNA AND THE EPITRANSCRIPTOME: HIDDEN FACTORS DIRECTING THE STRESS RESPONSE AND TAUOPATHY
Abstract
Aims
Tau is known to oligomerize and fibrillize, but the target of oligomeric tau (oTau) in the neuron is unclear. We sought to determine the protein interaction network for oTau, and then use this to understand the mechanisms of action of oTau.
Methods
Light induced Cry2 tau oligomerization was combined with mass spectrometry to generate the oTau protein interaction network. Subsequent work used immunochemical methods with human and mouse brains, combined with knockdown in P301S tau mice.
Results
HNRNPA2B1, an indirect reader for N6-methyl adenosine (m6A), was the top oTau network member. The oTau::HNRNPA2B1::m6A complex was validated by imaging and immunoprecipitation in human and mouse brains. oTau co-localized with m6A in a disease-dependent manner, increasing with disease progression over 4-fold in P301S tau mice and in human cases of Alzheimer’s disease. Colocalization of oTau with m6A (as well as HNRNPA2B1) was confirmed by proximity ligation assays. We will present transcripts and circRNAs that exhibit disease-dependent differential methylation. Knockdown of HNRNPA2B1 or m6A reduced the complex, rescued protein synthesis and inhibited neurodegeneration in P301S tau mice.
Conclusions
Little is known about the role of m6A in neurodegenerative diseases. These results identify a novel complex containing oTau, HNRNPA2B1 and m6A that contributes to the integrated stress response and the pathophysiology of oTau. The protection arising from knockdown of the oTau::HNRNPA2B1::m6A complex components suggests that this complex plays an important role in disease progression. Discovery of robust disease-dependent increases of m6A in AD opens novel areas of investigation and presents a novel target for diagnosis and therapy.