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Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain

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Abstract

Mutations in the fused in sarcoma (FUS) gene are linked to a form of familial amyotrophic lateral sclerosis (ALS), ALS6. The FUS protein is a major component of the ubiquitin-positive neuronal cytoplasmic inclusions in both ALS6 and some rare forms of frontotemporal lobar degeneration (FTLD). The latter are now collectively referred to as FTLD-FUS. In the present study, we investigated the localization of FUS in human and mouse brains. FUS was detected by western blot as an approximately 72 kDa protein in both human and mouse brains. Immunohistochemistry using lightly fixed tissue sections of human and mouse brains revealed FUS-positive granular staining in the neuropil, in addition to nuclear staining. Such granules are abundant in the gray matter of the brainstem and spinal cord. They are not frequent in the telencephalon. At the light microscopic level, FUS-positive granules are often co-localized with synaptophysin and present in association with microtubule-associated protein 2-positive dendrites. In the synaptosomal fraction of mouse brain, FUS is detected mainly in the post-synaptic density fraction. Thus, while FUS is primarily a nuclear protein, it may also play a role in dendrites. In the brains of patients with FTLD with TDP-43 deposition (FTLD-TDP), the number of FUS-positive granules in the cortex is increased compared with control cases. The increase in Alzheimer’s disease (AD) is less remarkable but still significant. The dendritic localization of FUS and its increase in FTLD-TDP and AD may have some implication for the pathophysiology of neurodegenerative diseases.

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Acknowledgments

The authors thank the patients and their families who made this research possible. We also thank Dr. Kenichi Oshima and Dr. Kazuhiro Niizato (Tokyo Metropolitan Matuzawa Hospital), Dr. Eizo Iseki (Juntendo Tokyo Koto Geriatric Medical Center) and Dr. Mitsumoto Onaya (National Hospital Organization Shimofusa Psychiatric Medical Center) to provide brain samples. This research was supported by Grants-in-Aid for Young Scientists, 23791008 (S.H.) of the Japan Society for the Promotion of Science; Grants-in-Aid from the Ministry of Health, Labor and Welfare10102894 and 10103470 (H.A.), and the Ministry of Education, Culture, Science 09019658 (H.A.), Japan.

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Authors and Affiliations

  1. Dementia Project, Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan

    Naoya Aoki, Shinji Higashi, Ito Kawakami, Zen Kobayashi, Masato Hosokawa & Haruhiko Akiyama

  2. Department of Psychiatry, Yokohama City University School of Medicine, Yokohama, Japan

    Naoya Aoki, Ito Kawakami, Omi Katsuse, Takashi Togo & Yoshio Hirayasu

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  1. Naoya Aoki
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  2. Shinji Higashi
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Correspondence to Haruhiko Akiyama.

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401_2012_984_MOESM1_ESM.tiff

Supplementary material 1 FUS immunostaining of the frontal cortex (a, b) and the substantia nigra pars compacta (SNpc) (c, d) from a control subject. Antibodies used are HPA-008784 (a, c) and A300-293A (b, d). The subsequences against which each antibody was made are shown in Fig. 1. With all antibodies, nuclear staining predominates in the frontal cortex, while neuropil granules are abundant in the SNpc. Inserts in c and d show higher power magnification of the boxed area. a to d are at the same magnification. Scale bar = 50 μm in a. (TIFF 4246 kb)

Supplementary material 2 (DOCX 19 kb)

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Aoki, N., Higashi, S., Kawakami, I. et al. Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain. Acta Neuropathol 124, 383–394 (2012). https://doi.org/10.1007/s00401-012-0984-6

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  • DOI: https://doi.org/10.1007/s00401-012-0984-6

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