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

Fingerprint

Spinal Muscular Atrophy
Hydrolases
Ubiquitin
Homeostasis
Therapeutics
Pharmacology
Muscular Atrophy
Neuromuscular Junction
Motor Neurons
Dimethyl Sulfoxide
Fibroblasts
Pathology
Neurons
Weights and Measures
Survival
Enzymes

Keywords

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

Cite this

@article{a50ec87134a7479eb92ff4f367bd2f08,
title = "Increased levels of UCHL1 are a compensatory response to disrupted ubiquitin homeostasis in spinal muscular atrophy and do not represent a viable therapeutic target",
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.",
keywords = "UCHL1, spinal muscular atrophy, disease pathogenesis, motor neurone loss",
author = "Rachael Powis and Chantal Mutsaers and Thomas Wishart and Gillian Hunter and Brunhilde Wirth and Thomas Gillingwater",
note = "Document provided not opening - query to author 30-11-15 ET",
year = "2014",
month = "12",
doi = "10.1111/nan.12168",
language = "English",
volume = "40",
pages = "873--887",
journal = "Neuropathology and Applied Neurobiology",
issn = "0305-1846",
publisher = "John Wiley & Sons",
number = "7",

}

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 journalArticle

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 -