Abstract
| Original language | English |
|---|---|
| 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 |
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Keywords
- UCHL1
- spinal muscular atrophy
- disease pathogenesis
- motor neurone loss
Cite this
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Increased levels of UCHL1 are a compensatory response to disrupted ubiquitin homeostasis in spinal muscular atrophy and do not represent a viable therapeutic target. / Powis, Rachael; Mutsaers, Chantal; Wishart, Thomas; Hunter, Gillian; Wirth, Brunhilde; Gillingwater, Thomas.
In: Neuropathology and Applied Neurobiology, Vol. 40, No. 7, 12.2014, p. 873-887.Research output: Contribution to journal › Article
TY - JOUR
T1 - Increased levels of UCHL1 are a compensatory response to disrupted ubiquitin homeostasis in spinal muscular atrophy and do not represent a viable therapeutic target
AU - Powis, Rachael
AU - Mutsaers, Chantal
AU - Wishart, Thomas
AU - Hunter, Gillian
AU - Wirth, Brunhilde
AU - Gillingwater, Thomas
N1 - Document provided not opening - query to author 30-11-15 ET
PY - 2014/12
Y1 - 2014/12
N2 - 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.
AB - 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.
KW - UCHL1
KW - spinal muscular atrophy
KW - disease pathogenesis
KW - motor neurone loss
U2 - 10.1111/nan.12168
DO - 10.1111/nan.12168
M3 - Article
VL - 40
SP - 873
EP - 887
JO - Neuropathology and Applied Neurobiology
JF - Neuropathology and Applied Neurobiology
SN - 0305-1846
IS - 7
ER -