Targeting MSUT2 with small molecules to ameliorate pathological tau

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Abstract In frontotemporal lobar degeneration, Alzheimer’s disease (AD) and related tauopathies, tau neuropathology correlates with severity of dementia. However, interventions for AD and AD related dementias (ADRDs) are largely limited to treatment of symptoms that do not directly alter tau pathology or the resultant neurodegeneration, with only one Aβ-directed immunotherapeutic (Aduhelm) recently receiving a controversial accelerated approval for disease modification. Although investigation into additional Aβ targeted immunotherapies continues, the obvious need remains for the development of tau-targeted disease-modifying therapeutics. Our work has demonstrated that MSUT2 controls neuronal susceptibility to tau toxicity in the mammalian brain. The mechanism of MSUT2 modulation of tauopathy involves the MSUT2 CCCH domain binding to poly(A) RNA, as deletion of the CCCH domain prevents neurodegeneration in animal models of tauopathy. High throughput screening of over 100,000 high diversity compounds has identified many active dose- responsive compounds that inhibit MSUT2 poly(A) RNA binding activity, including several classes of compounds exhibiting promising structure-activity relationships. The identification of drug-like small molecules that inhibit MSUT2 binding to poly(A) RNA will provide a pharmacological means of intervening against tauopathy. We hypothesize that small-molecule inhibitors of MSUT2/poly(A) RNA binding will slow or reverse tau pathology and the toxic consequences of pathological tau. The specific aims of this proposal are to optimize potent and specific brain-penetrant MSUT2 inhibitors and use them to demonstrate proof-of-concept therapeutic approaches to treating tauopathy. Successful completion of these aims will set the stage for future translational studies by both generating MSUT2 specific tool compounds and further validating a novel therapeutic target for pharmacological intervention in tauopathy disorders.