Aberrant membranes and double-membrane structures accumulate in the Axons of Atg5-null Purkinje cells before neuronal death

被引:135
作者
Nishiyama, Jun
Miura, Erika
Mizushima, Noboru
Watanabe, Masahiko
Yuzaki, Michisuke
机构
[1] Keio Univ, Sch Med, Dept Physiol, Shinjuku Ku, Tokyo 1608582, Japan
[2] Univ Tokyo, Fac Med, Dept Neuropsychiat, Tokyo 113, Japan
[3] Hokkaido Univ, Sch Med, Dept Anat, Sapporo, Hokkaido 060, Japan
[4] Tokyo Med & Dent Univ, Dept Cellular Physiol, Tokyo, Japan
关键词
autophagosome; Atg5; Purkinje cell; cerebellum; mouse; axon; neurodegeneration;
D O I
10.4161/auto.4964
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Autophagy (macroautophagy) is an evolutionally conserved process by which cytoplasmic proteins and organelles are surrounded by unique double membranes and are subsequently degraded upon fusion with lysosomes. Many autophagy-related genes (Atg) have been identified in yeast; a ubiquitin-like Atg 12-Atg5 system is also essential for the elongation of the isolation membrane in mammalian cells. Nevertheless, the regulation of autophagy in neurons remains largely unknown. In this study, we crossed conditional knockout mice Atg5(flox/flox) with pcp2-Cre transgenic mice, which express Cre recombinase through a Purkinje cell-specific promoter, pcp2. In Atg5(flox/flox); pcp2-Cre mice, the Atg5 gene was excised as early as postnatal day 6; Purkinje cells started to degenerate after approximately 8 weeks, and the animals showed an ataxic gait from around 10 months. Initially, however, the Purkinje cells showed axonal swelling around its terminals from as early as 4 weeks after birth. An electron microscopic analysis revealed the accumulation of autophagosome-like double-membrane structures in the swollen regions, together with numerous membranous organelles, such as tubular or sheet-like smooth endoplasmic reticulum and vesicles. These results suggest that Atg5 plays important roles in the maintenance of axon morphology and membrane structures, and its loss of function leads to the swelling of axons, followed by progressive neurodegeneration in mammalian neurons.
引用
收藏
页码:591 / 596
页数:6
相关论文
共 24 条
  • [1] Barski JJ, 2000, GENESIS, V28, P93, DOI 10.1002/1526-968X(200011/12)28:3/4<93::AID-GENE10>3.0.CO
  • [2] 2-W
  • [3] Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes
    Bowman, Aaron B.
    Lam, Yung C.
    Jafar-Nejad, Paymaan
    Chen, Hung-Kai
    Richman, Ronald
    Samaco, Rodney C.
    Fryer, John D.
    Kahle, Juliette J.
    Orr, Harry T.
    Zoghbi, Huda Y.
    [J]. NATURE GENETICS, 2007, 39 (03) : 373 - 379
  • [4] Axon degeneration mechanisms: Commonality amid diversity
    Coleman, M
    [J]. NATURE REVIEWS NEUROSCIENCE, 2005, 6 (11) : 889 - 898
  • [5] EARLY DEVELOPMENT OF THE LURCHER CEREBELLUM - PURKINJE-CELL ALTERATIONS AND IMPAIRMENT OF SYNAPTOGENESIS
    DUMESNILBOUSEZ, N
    SOTELO, C
    [J]. JOURNAL OF NEUROCYTOLOGY, 1992, 21 (07): : 506 - 529
  • [6] The putative neural stem cell marker, nestin, is expressed in heterogeneous cell types in the adult rat neocortex
    Ernst, C
    Christie, BR
    [J]. NEUROSCIENCE, 2006, 138 (01) : 183 - 188
  • [7] Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice
    Hara, Taichi
    Nakamura, Kenji
    Matsui, Makoto
    Yamamoto, Akitsugu
    Nakahara, Yohko
    Suzuki-Migishima, Rika
    Yokoyama, Minesuke
    Mishima, Kenji
    Saito, Ichiro
    Okano, Hideyuki
    Mizushima, Noboru
    [J]. NATURE, 2006, 441 (7095) : 885 - 889
  • [8] PRODUCTS OF ENDOCYTOSIS AND AUTOPHAGY ARE RETRIEVED FROM AXONS BY REGULATED RETROGRADE ORGANELLE TRANSPORT
    HOLLENBECK, PJ
    [J]. JOURNAL OF CELL BIOLOGY, 1993, 121 (02) : 305 - 315
  • [9] A ubiquitin-like system mediates protein lipidation
    Ichimura, Y
    Kirisako, T
    Takao, T
    Satomi, Y
    Shimonishi, Y
    Ishihara, N
    Mizushima, N
    Tanida, I
    Kominami, E
    Ohsumi, M
    Noda, T
    Ohsumi, Y
    [J]. NATURE, 2000, 408 (6811) : 488 - 492
  • [10] A unified nomenclature for yeast autophagy-related genes
    Klionsky, DJ
    Cregg, JM
    Dunn, WA
    Emr, SD
    Sakai, Y
    Sandoval, IV
    Sibirny, A
    Subramani, S
    Thumm, M
    Veenhuis, M
    Ohsumi, Y
    [J]. DEVELOPMENTAL CELL, 2003, 5 (04) : 539 - 545