Increased levels of UCHL1 are a compensatory response to disrupted ubiquitin homeostasis in spinal muscular atrophy and do not represent a viable therapeutic target

Rachael Powis, Chantal Mutsaers, Thomas Wishart, Gillian Hunter, Brunhilde Wirth, Thomas Gillingwater

Research output: Contribution to journalArticle

Abstract

Levels of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) are robustly increased in spinal muscular atrophy (SMA) patient fibroblasts and mouse models. We therefore wanted to establish whether changes in UCHL1 contribute directly to disease pathogenesis, and to assess whether pharmacological inhibition of UCHL1 represents a viable therapeutic option for SMA. SMA mice and control littermates received a pharmacological UCHL1 inhibitor (LDN-57444) or DMSO vehicle. Survival and weight were monitored daily, a righting test of motor performance was performed, and motor neurone loss, muscle fibre atrophy and neuromuscular junction pathology were all quantified. Ubiquitin-like modifier activating enzyme 1 (Uba1) was then pharmacologically inhibited in neurones in vitro to examine the relationship between Uba1 levels and UCHL1 in SMA.
Original languageEnglish
Pages (from-to)873-887
Number of pages15
JournalNeuropathology and Applied Neurobiology
Volume40
Issue number7
Early online date17 Nov 2014
DOIs
Publication statusPublished - Dec 2014

Keywords

  • UCHL1
  • spinal muscular atrophy
  • disease pathogenesis
  • motor neurone loss

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