{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T03:09:45Z","timestamp":1791169785655,"version":"4.1.0"},"reference-count":59,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2014,11,17]],"date-time":"2014-11-17T00:00:00Z","timestamp":1416182400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100012070","name":"Anatomical Society","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012070","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Muscular Dystrophy Campaign"},{"name":"SMA Trust"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2014,12]]},"abstract":"Aim<\/jats:title>Levels of ubiquitin carboxyl\u2010terminal hydrolase L<\/jats:styled-content>1 (UCHL<\/jats:styled-content>1) are robustly increased in spinal muscular atrophy (SMA<\/jats:styled-content>) patient fibroblasts and mouse models. We therefore wanted to establish whether changes in UCHL<\/jats:styled-content>1 contribute directly to disease pathogenesis, and to assess whether pharmacological inhibition of UCHL<\/jats:styled-content>1 represents a viable therapeutic option for SMA<\/jats:styled-content>.<\/jats:p><\/jats:sec>Methods<\/jats:title>SMA<\/jats:styled-content> mice and control littermates received a pharmacological UCHL<\/jats:styled-content>1 inhibitor (LDN<\/jats:styled-content>\u201057444) or DMSO<\/jats:styled-content> 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\u2010like modifier activating enzyme 1 (Uba<\/jats:styled-content>1) was then pharmacologically inhibited in neurones in vitro<\/jats:italic> to examine the relationship between Uba<\/jats:styled-content>1 levels and UCHL<\/jats:styled-content>1 in SMA<\/jats:styled-content>.<\/jats:p><\/jats:sec>Results<\/jats:title>Pharmacological inhibition of UCHL<\/jats:styled-content>1 failed to improve survival, motor symptoms or neuromuscular pathology in SMA<\/jats:styled-content> mice and actually precipitated the onset of weight loss. LDN<\/jats:styled-content>\u201057444 treatment significantly decreased spinal cord mono\u2010ubiquitin levels, further exacerbating ubiquitination defects in SMA<\/jats:styled-content> mice. Pharmacological inhibition of Uba<\/jats:styled-content>1, levels of which are robustly reduced in SMA<\/jats:styled-content>, was sufficient to induce accumulation of UCHL<\/jats:styled-content>1 in primary neuronal cultures.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Pharmacological inhibition of UCHL<\/jats:styled-content>1 exacerbates rather than ameliorates disease symptoms in a mouse model of SMA<\/jats:styled-content>. Thus, pharmacological inhibition of UCHL<\/jats:styled-content>1 is not a viable therapeutic target for SMA<\/jats:styled-content>. Moreover, increased levels of UCHL<\/jats:styled-content>1 in SMA<\/jats:styled-content> likely represent a downstream consequence of decreased Uba<\/jats:styled-content>1 levels, indicative of an attempted supportive compensatory response to defects in ubiquitin homeostasis caused by low levels of SMN<\/jats:styled-content> protein.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12168","type":"journal-article","created":{"date-parts":[[2014,7,8]],"date-time":"2014-07-08T07:44:51Z","timestamp":1404805491000},"page":"873-887","source":"Crossref","is-referenced-by-count":31,"title":["Increased levels of UCHL<\/scp>1 are a compensatory response to disrupted ubiquitin homeostasis in spinal muscular atrophy and do not represent a viable therapeutic target"],"prefix":"10.1111","volume":"40","author":[{"given":"Rachael A.","family":"Powis","sequence":"first","affiliation":[{"name":"Euan MacDonald Centre for Motor Neurone Disease Research University of Edinburgh Edinburgh UK"},{"name":"Centre for Integrative Physiology University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal A.","family":"Mutsaers","sequence":"additional","affiliation":[{"name":"Euan MacDonald Centre for Motor Neurone Disease Research University of Edinburgh Edinburgh UK"},{"name":"Centre for Integrative Physiology University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas. 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