NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization

Tomoyuki Yamanaka, Asako Tosaki, Masaru Kurosawa, Gen Matsumoto, Masato Koike, Yasuo Uchiyama, Sankar N. Maity, Tomomi Shimogori, Nobutaka Hattori and Nobuyuki Nukina ()
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Tomoyuki Yamanaka: Juntendo University Graduate School of Medicine
Asako Tosaki: Laboratory for Structural Neuropathology, RIKEN Brain Science Institute
Masaru Kurosawa: Juntendo University Graduate School of Medicine
Gen Matsumoto: Juntendo University Graduate School of Medicine
Masato Koike: Juntendo University Graduate School of Medicine
Yasuo Uchiyama: Juntendo University Graduate School of Medicine
Sankar N. Maity: The University of Texas MD Anderson Cancer Center
Tomomi Shimogori: Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute
Nobutaka Hattori: Juntendo University Graduate School of Medicine
Nobuyuki Nukina: Juntendo University Graduate School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: Abstract Nuclear transcription factor-Y (NF-Y), a key regulator of cell-cycle progression, often loses its activity during differentiation into nonproliferative cells. In contrast, NF-Y is still active in mature, differentiated neurons, although its neuronal significance remains obscure. Here we show that conditional deletion of the subunit NF-YA in postmitotic mouse neurons induces progressive neurodegeneration with distinctive ubiquitin/p62 pathology; these proteins are not incorporated into filamentous inclusion but co-accumulated with insoluble membrane proteins broadly on endoplasmic reticulum (ER). The degeneration also accompanies drastic ER disorganization, that is, an aberrant increase in ribosome-free ER in the perinuclear region, without inducing ER stress response. We further perform chromatin immunoprecipitation and identify several NF-Y physiological targets including Grp94 potentially involved in ER disorganization. We propose that NF-Y is involved in a unique regulation mechanism of ER organization in mature neurons and its disruption causes previously undescribed novel neuropathology accompanying abnormal ubiquitin/p62 accumulation.

Date: 2014
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DOI: 10.1038/ncomms4354

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