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 language | English |
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Pages (from-to) | 873-887 |
Number of pages | 15 |
Journal | Neuropathology and Applied Neurobiology |
Volume | 40 |
Issue number | 7 |
Early online date | 17 Nov 2014 |
DOIs | |
Publication status | Published - Dec 2014 |
Keywords
- UCHL1
- spinal muscular atrophy
- disease pathogenesis
- motor neurone loss