Research ArticleAlzheimer’s Disease

Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain

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Science Translational Medicine  18 Dec 2019:
Vol. 11, Issue 523, eaao6545
DOI: 10.1126/scitranslmed.aao6545

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RNA metabolism and abnormal tau in AD

Currently, there are no effective treatments for Alzheimer’s disease (AD) and related dementia disorders. Abnormal tau protein correlates with dementia, but the molecular mechanisms whereby tau abnormalities cause neuronal dysfunction and neurodegeneration remain unclear. Wheeler et al. now report that neurons in the brains of Msut2 knockout mice are protected from abnormal tau pathology. MSUT2 and PABPN1, two interacting proteins that facilitate RNA metabolism, were found to modulate the susceptibility of mice to the toxic consequences of abnormal tau deposition in the brain. The authors propose that MSUT2 and PABPN1 may act together to influence deposition of abnormal tau in AD.

Abstract

Brain lesions composed of pathological tau help to drive neurodegeneration in Alzheimer’s disease (AD) and related tauopathies. Here, we identified the mammalian suppressor of tauopathy 2 (MSUT2) gene as a modifier of susceptibility to tau toxicity in two mouse models of tauopathy. Transgenic PS19 mice overexpressing tau, a model of AD, and lacking the Msut2 gene exhibited decreased learning and memory deficits, reduced neurodegeneration, and reduced accumulation of pathological tau compared to PS19 tau transgenic mice expressing Msut2. Conversely, Msut2 overexpression in 4RTauTg2652 tau transgenic mice increased pathological tau deposition and promoted the neuroinflammatory response to pathological tau. MSUT2 is a poly(A) RNA binding protein that antagonizes the canonical nuclear poly(A) binding protein PABPN1. In individuals with AD, MSUT2 abundance in postmortem brain tissue predicted an earlier age of disease onset. Postmortem AD brain tissue samples with normal amounts of MSUT2 showed elevated neuroinflammation associated with tau pathology. We observed co-depletion of MSUT2 and PABPN1 in postmortem brain samples from a subset of AD cases with higher tau burden and increased neuronal loss. This suggested that MSUT2 and PABPN1 may act together in a macromolecular complex bound to poly(A) RNA. Although MSUT2 and PABPN1 had opposing effects on both tau aggregation and poly(A) RNA tail length, we found that increased poly(A) tail length did not ameliorate tauopathy, implicating other functions of the MSUT2/PABPN1 complex in tau proteostasis. Our findings implicate poly(A) RNA binding proteins both as modulators of pathological tau toxicity in AD and as potential molecular targets for interventions to slow neurodegeneration in tauopathies.

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