title: An early onset progressive motor neuron disorder in Scyl1-deficient mice is associated with mislocalization of TDP-43.
abstract: 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.
authors.affiliation: Department of Biochemistry, Advanced Histology Core, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. stephane.pelletier@stjude.org
authors.forename: Stephane
authors.initials: S
authors.lastname: Pelletier
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gingras
authors.forename: Sherie
authors.initials: S
authors.lastname: Howell
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: James N
authors.initials: JN
authors.lastname: Ihle
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology; D000818:Animals; D000071183:Autophagy-Related Proteins; D015153:Blotting, Western; D002999:Clone Cells / Q000502:physiology; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018737:Hand Strength / Q000502:physiology; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000648:ultrastructure; D008969:Molecular Sequence Data; D016472:Motor Neuron Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009046:Motor Neurons / Q000502:physiology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000473:pathology; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; D004268:DNA-Binding Proteins; C523633:Scyl1 protein, mouse; C538988:UBQLN2 protein, mouse; D004247:DNA; D011494:Protein Kinases