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

Jun Nishiyama, Eriko Miura, Noboru Mizushima, Masahiko Watanabe, Michisuke Yuzaki

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

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 Atg12-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.

Original languageEnglish
Pages (from-to)591-596
Number of pages6
JournalAutophagy
Volume3
Issue number6
DOIs
Publication statusPublished - 2007

Keywords

  • Atg5
  • Autophagosome
  • Axon
  • Cerebellum
  • Mouse
  • Neurodegeneration
  • Purkinje cell

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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