| First Author | Pelletier S | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 47 | Pages | 16560-73 |
| PubMed ID | 23175812 | Mgi Jnum | J:192445 |
| Mgi Id | MGI:5465201 | Doi | 10.1523/JNEUROSCI.1787-12.2012 |
| Citation | Pelletier S, et al. (2012) An early onset progressive motor neuron disorder in Scyl1-deficient mice is associated with mislocalization of TDP-43. J Neurosci 32(47):16560-73 |
| abstractText | The molecular and cellular bases of motor neuron diseases (MNDs) are still poorly understood. The diseases are mostly sporadic, with ~10% 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 Scyl1, 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 Scyl1(-/-) 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 Scyl1(-/-) 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 Scyl1 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 Scyl1 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 Scyl1(-/-) mice share pathological features with many human neurodegenerative conditions. |
