Motor neuron-specific disruption of proteasomes, but not autophagy, replicates amyotrophic lateral sclerosis

Yoshitaka Tashiro, Makoto Urushitani, Haruhisa Inoue, Masato Koike, Yasuo Uchiyama, Masaaki Komatsu, Keiji Tanaka, Maya Yamazaki, Manabu Abe, Hidemi Misawa, Kenji Sakimura, Hidefumi Ito, Ryosuke Takahashia

Research output: Contribution to journalArticlepeer-review

114 Citations (Scopus)

Abstract

Evidence suggests that protein misfolding is crucially involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, controversy still exists regarding the involvement of proteasomes or autophagy in ALS due to previous conflicting results. Here, we show that impairment of the ubiquitin-proteasome system, but not the autophagy-lysosome system in motor neurons replicates ALS in mice. Conditional knock-out mice of the proteasome subunit Rpt3 in a motor neuron-specific manner (Rpt3-CKO) showed locomotor dysfunction accompanied by progressive motor neuron loss and gliosis. Moreover, diverse ALS-linked proteins, including TAR DNA-binding protein 43 kDa (TDP-43), fused in sarcoma (FUS), ubiquilin 2, and optineurin were mislocalized or accumulated in motor neurons, together with other typical ALS hallmarks such as basophilic inclusion bodies. On the other hand, motor neuron-specific knock-out of Atg7, a crucial component for the induction of autophagy (Atg7-CKO), only resulted in cytosolic accumulation of ubiquitin and p62, and no TDP-43 or FUS pathologies or motor dysfunction was observed. These results strongly suggest that proteasomes, but not autophagy, fundamentally govern the development of ALS in which TDP-43 and FUS proteinopathy may play a crucial role. Enhancement of proteasome activity may be a promising strategy for the treatment of ALS.

Original languageEnglish
Pages (from-to)42984-42994
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number51
DOIs
Publication statusPublished - 2012 Dec 14

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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