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      Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes.

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          Abstract

          Fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) are RNA binding proteins that regulate RNA metabolism. We found that alternative splicing of the Mapt gene at exon 10, which generates 4-repeat tau (4R-T) and 3-repeat tau (3R-T), is regulated by interactions between FUS and SFPQ in the nuclei of neurons. Hippocampus-specific FUS- or SFPQ-knockdown mice exhibit frontotemporal lobar degeneration (FTLD)-like behaviors, reduced adult neurogenesis, accumulation of phosphorylated tau, and hippocampal atrophy with neuronal loss through an increased 4R-T/3R-T ratio. Normalization of this increased ratio by 4R-T-specific silencing results in recovery of the normal phenotype. These findings suggest a biological link among FUS/SFPQ, tau isoform alteration, and phenotypic expression, which may function in the early pathomechanism of FTLD.

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          Author and article information

          Journal
          Cell Rep
          Cell reports
          Elsevier BV
          2211-1247
          Jan 31 2017
          : 18
          : 5
          Affiliations
          [1 ] Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Department of Therapeutics for Intractable Neurological Disorders, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan. Electronic address: ishigaki-ns@umin.net.
          [2 ] Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
          [3 ] Department of Neurology, Aichi Medical University, School of Medicine, Aichi 480-1195, Japan.
          [4 ] Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Aichi 480-1195, Japan.
          [5 ] Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
          [6 ] Faculty of Science, Gakushuin University, Toshima-ku, Tokyo 171-8588, Japan.
          [7 ] Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
          [8 ] Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Aichi 480-1195, Japan.
          [9 ] Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
          [10 ] Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Brain and Mind Research Center, Nagoya University, Nagoya, Aichi 466-8550, Japan.
          [11 ] Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
          [12 ] Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Brain and Mind Research Center, Nagoya University, Nagoya, Aichi 466-8550, Japan; Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan. Electronic address: sobueg@med.nagoya-u.ac.jp.
          Article
          S2211-1247(17)30045-1
          10.1016/j.celrep.2017.01.013
          28147269
          5260d33c-b0cd-4e68-8c26-c64caa13829a
          History

          FUS,SFPQ,adult neurogenesis,tau,FTLD
          FUS, SFPQ, adult neurogenesis, tau, FTLD

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