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

TitleActivity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain.
Publication TypeJournal Article
Year of Publication2019
AuthorsWheeler JM, McMillan P, Strovas TJ, Liachko NF, Amlie-Wolf A, Kow RL, Klein RL, Szot P, Robinson L, Guthrie C, Saxton A, Kanaan NM, Raskind M, Peskind E, Trojanowski JQ, M Y Lee V, San Wang L-, C Keene D, Bird T, Schellenberg GD, Kraemer B
JournalSci Transl Med
Date Published2019 12 18

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 () 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 gene exhibited decreased learning and memory deficits, reduced neurodegeneration, and reduced accumulation of pathological tau compared to PS19 tau transgenic mice expressing Conversely, 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.

Alternate JournalSci Transl Med
PubMed ID31852801
Grant ListI01 BX000877 / BX / BLRD VA / United States
P50 AG005136 / AG / NIA NIH HHS / United States
R01 NS064131 / NS / NINDS NIH HHS / United States
P01 AG017586 / AG / NIA NIH HHS / United States
RF1 AG055474 / AG / NIA NIH HHS / United States