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

Autor:	Brunhilde Wirth, Gillian Hunter, Thomas H. Gillingwater, Chantal A. Mutsaers, Thomas M. Wishart, Rachael A. Powis
Rok vydání:	2014
Předmět:	medicine.medical_specialty Histology biology Ubiquitin homeostasis UBA1 Spinal muscular atrophy Motor neuron SMA medicine.disease Neuromuscular junction Pathology and Forensic Medicine medicine.anatomical_structure Endocrinology Neurology Ubiquitin Biochemistry Physiology (medical) Internal medicine medicine biology.protein Neurology (clinical) Homeostasis
Zdroj:	Neuropathology and Applied Neurobiology. 40:873-887
ISSN:	0305-1846
DOI:	10.1111/nan.12168
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::0c2cb755b1b1d9bde5e4fdf5924350c0 https://doi.org/10.1111/nan.12168 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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