{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T21:41:28Z","timestamp":1791063688188,"version":"4.1.0"},"reference-count":60,"publisher":"Society for Neuroscience","issue":"47","license":[{"start":{"date-parts":[[2013,5,21]],"date-time":"2013-05-21T00:00:00Z","timestamp":1369094400000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"accepted":{"date-parts":[[2012,9,17]]},"published-print":{"date-parts":[[2012,11,21]]},"abstract":"<jats:p>The molecular and cellular bases of motor neuron diseases (MNDs) are still poorly understood. The diseases are mostly sporadic, with \u223c10% of cases being familial. In most cases of familial motor neuronopathy, the disease is caused by either gain-of-adverse-effect mutations or partial loss-of-function mutations in ubiquitously expressed genes that serve essential cellular functions. Here we show that deletion of<jats:italic>Scyl1<\/jats:italic>, an evolutionarily conserved and ubiquitously expressed gene encoding the COPI-associated protein pseudokinase SCYL1, causes an early onset progressive MND with characteristic features of amyotrophic lateral sclerosis (ALS). Skeletal muscles of<jats:italic>Scyl1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice displayed neurogenic atrophy, fiber type switching, and disuse atrophy. Peripheral nerves showed axonal degeneration. Loss of lower motor neurons (LMNs) and large-caliber axons was conspicuous in<jats:italic>Scyl1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>animals. Signs of neuroinflammation were seen throughout the CNS, most notably in the ventral horn of the spinal cord. Neural-specific, but not skeletal muscle-specific, deletion of<jats:italic>Scyl1<\/jats:italic>was sufficient to cause motor dysfunction, indicating that SCYL1 acts in a neural cell-autonomous manner to prevent LMN degeneration and motor functions. Remarkably, deletion of<jats:italic>Scyl1<\/jats:italic>resulted in the mislocalization and accumulation of TDP-43 (TAR DNA-binding protein of 43 kDa) and ubiquilin 2 into cytoplasmic inclusions within LMNs, features characteristic of most familial and sporadic forms of ALS. Together, our results identify SCYL1 as a key regulator of motor neuron survival, and<jats:italic>Scyl1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice share pathological features with many human neurodegenerative conditions.<\/jats:p>","DOI":"10.1523\/jneurosci.1787-12.2012","type":"journal-article","created":{"date-parts":[[2012,11,21]],"date-time":"2012-11-21T18:03:53Z","timestamp":1353521033000},"page":"16560-16573","source":"Crossref","is-referenced-by-count":41,"title":["An Early Onset Progressive Motor Neuron Disorder in<i>Scyl1<\/i>-Deficient Mice Is Associated with Mislocalization of 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