Universität zu Köln

Powis, R. A., Mutsaers, C. A., Wishart, T. M., Hunter, G., Wirth, B. and Gillingwater, T. H. (2014). Increased levels of UCHL1 are a compensatory response to disrupted ubiquitin homeostasis in spinal muscular atrophy and do not represent a viable therapeutic target. Neuropathol. Appl. Neurobiol., 40 (7). S. 873 - 888. HOBOKEN: WILEY-BLACKWELL. ISSN 1365-2990

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Abstract

AimLevels 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. MethodsSMA 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. ResultsPharmacological 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. ConclusionPharmacological 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Powis, R. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mutsaers, C. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wishart, T. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hunter, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirth, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gillingwater, T. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-422756
DOI:	10.1111/nan.12168
Journal or Publication Title:	Neuropathol. Appl. Neurobiol.
Volume:	40
Number:	7
Page Range:	S. 873 - 888
Date:	2014
Publisher:	WILEY-BLACKWELL
Place of Publication:	HOBOKEN
ISSN:	1365-2990
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TERMINAL HYDROLASE L1; PARKINSONS-DISEASE SUSCEPTIBILITY; WERDNIG-HOFFMANN DISEASE; SMN2 COPY NUMBER; MOTOR-NEURON; PROTEASOME SYSTEM; NEURODEGENERATIVE DISEASES; DEUBIQUITINATING ENZYMES; NEUROMUSCULAR-JUNCTION; S18Y POLYMORPHISM Multiple languages Clinical Neurology; Neurosciences; Pathology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42275