• Top page
  • Timetable
  • Per session
  • Per presentation
  • How to
  • Meeting Planner



Posttranslational Modulation and Proteolysis

開催日 2014/9/13
時間 11:00 - 12:00
会場 Poster / Exhibition(Event Hall B)

Selective autophagy of lysosomes with ceroid-lipofuscin in neurons deficient in cathepsinD

  • P3-045
  • 七尾 友久 / Tomohisa Nanao:1 小池 正人 / Koike Masato:2 山口 隼司 / Yamaguchi Junji:1 柴田 昌宏 / Shibata Masahiro:3 内山 安男 / Uchiyama Yasuo:1 
  • 1:順天堂大学大学院・医・神経疾患病態構造学 / Dept. Cell & Mol. Neuropathol., Juntendo Univ. Sch. Med. , Tokyo, Japan  2:順天堂大学大学院・医・神経生物学・形態学 / Dept. Cell Biol & Neurosci., Juntendo Univ. Sch. Med., Tokyo, Japan 3:新潟大学・医・肉眼解剖 / Division of Gross Anatomy and Morphogenesis, Niigata Univ. Sch. Med & Dent Sci., Niigata, Japan 

p62 and NBR1, adaptor proteins for selective autophagy, have binding regions with ubiquitin and LC3 on the isolation membrane of autophagosomes (AP). We have previously shown that mice deficient in lysosomal cathepsin D (CD) exhibit a new form of lysosomal accumulation disease with a phenotype resembling neuronal ceroid lipofuscinosis (NCL). Electron microscopic observations revealed accumulation of granular osmiophilic deposits (GRODs) and AP, morphological hallmarks of NCL, in the perikarya of neurons deficient in CD. Since GRODs were frequently found within AP that were localized in the perikarya of CD-deficient neurons, we speculated that enwrapment of GRODs into AP is due to selective autophagy. By immunostaining at the light and electron microscopic levels, ubiquitin was found to be colocalized with LC3, p62, and NBR1 in CD-deficient neurons, while gold particles for ubiquitin was detected on the membrane of GRODs together with those for p62 or NBR1. In CD-deficient neurons, GRODs, p62 and NBR1 were found only in somatodendritic portions but not in axons and their terminals. When triple knockout mice of CD, p62 and NBR1 in mouse brains were produced and analyzed, GRODs were not detected in AP of the neurons. In primary cultured neurons obtained from mouse embryonic cerebral cortex at E16, Lysotracker red-positive acidic compartments were largely localized in cell bodies and dendrites at 10 days after the start of cultures (DIV), although such positive vesicles were abundantly present in axons and filopodia at 3 DIV. Moreover, not only endogenous p62 and NBR1 but also GFP-tagged p62 and NBR1 were detected only in cell bodies and dendrites but not in the distal part of axons beyond the ankyrin G-positive initial segment. These results indicate that AP is non-selectively formed in the axons and axon terminals, while it is retrogradely sent back to the cell bodies of neurons where it receives lysosomal enzymes and become autolysosomes.

Copyright © Neuroscience2014. All Right Reserved.