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 A Powis, Chantal A Mutsaers, Thomas M Wishart, Gillian Hunter, Brunhilde Wirth, Thomas H Gillingwater

Research output: Contribution to journalArticlepeer-review

Abstract

AIM: 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.

METHODS: 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 neuron loss, muscle fibre atrophy and neuromuscular junction pathology were all quantified. Ubiquitin-like modifier activating enzyme 1 (Uba1) was then pharmacologically inhibited in neurons in vitro to examine the relationship between Uba1 levels and UCHL1 in SMA.

RESULTS: Pharmacological inhibition of UCHL1 failed to improve survival, motor symptoms, or neuromuscular pathology in SMA mice and actually precipitated the onset of weight loss. LDN-57444 treatment significantly decreased spinal cord mono-ubiquitin levels, further exacerbating ubiquitination defects in SMA mice. Pharmacological inhibition of Uba1, levels of which are robustly reduced in SMA, was sufficient to induce accumulation of UCHL1 in primary neuronal cultures.

CONCLUSION: Pharmacological inhibition of UCHL1 exacerbates rather than ameliorates disease symptoms in a mouse model of SMA. Thus, pharmacological inhibition of UCHL1 is not a viable therapeutic target for SMA. Moreover, increased levels of UCHL1 in SMA likely represent a downstream consequence of decreased Uba1 levels, indicative of an attempted supportive compensatory response to defects in ubiquitin homeostasis caused by low levels of SMN protein.

Original languageEnglish
Pages (from-to)873-887
Number of pages15
JournalNeuropathology and Applied Neurobiology
Volume40
Issue number7
Early online date8 Jul 2014
DOIs
Publication statusPublished - 8 Jul 2014

Keywords

  • SMA
  • spinal muscular atrophy
  • Uba1
  • ubiquitin
  • UCHL1
  • TERMINAL HYDROLASE L1
  • PARKINSONS-DISEASE SUSCEPTIBILITY
  • WERDNIG-HOFFMANN DISEASE
  • SMN2 COPY NUMBER
  • MOTOR-NEURON
  • PROTEASOME SYSTEM
  • NEURODEGENERATIVE DISEASES
  • DEUBIQUITINATING ENZYMES
  • NEUROMUSCULAR-JUNCTION
  • S18Y POLYMORPHISM

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