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

© 2014 British Neuropathological Society..

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 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.

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.

Media Type:

Electronic Article

Year of Publication:

2014

Publication:

2014

Contained In:

To Main Record - volume:40

Contained In:

Neuropathology and applied neurobiology - 40(2014), 7 vom: 06. Dez., Seite 873-87

Language:

English

Contributors:

Powis, Rachael A [Author]
Mutsaers, Chantal A [Author]
Wishart, Thomas M [Author]
Hunter, Gillian [Author]
Wirth, Brunhilde [Author]
Gillingwater, Thomas H [Author]

Links:

Volltext

Keywords:

EC 3.4.19.12
Indoles
Journal Article
LDN 57444
Oximes
Research Support, Non-U.S. Gov't
SMA
Smn1 protein, mouse
Spinal muscular atrophy
Survival of Motor Neuron 1 Protein
UCHL1
Uba1
Ubiquitin
Ubiquitin Thiolesterase
Uchl1 protein, mouse

Notes:

Date Completed 30.10.2015

Date Revised 25.11.2016

published: Print

Citation Status MEDLINE

doi:

10.1111/nan.12168

funding:

Supporting institution / Project title:

PPN (Catalogue-ID):

NLM24022843X