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An early onset progressive motor neuron disorder in Scyl1-deficient mice is associated with mislocalization of TDP-43.

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.

Pubmed ID: 23175812


  • Pelletier S
  • Gingras S
  • Howell S
  • Vogel P
  • Ihle JN


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

November 21, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: CA21765
  • Agency: NHLBI NIH HHS, Id: P01 HL53740
  • Agency: NIDDK NIH HHS, Id: R01DK42932

Mesh Terms

  • Adaptor Proteins, Vesicular Transport
  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis
  • Animals
  • Blotting, Western
  • Clone Cells
  • DNA
  • DNA-Binding Proteins
  • Hand Strength
  • Immunohistochemistry
  • Inclusion Bodies
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Mitochondria
  • Molecular Sequence Data
  • Motor Neuron Disease
  • Motor Neurons
  • Muscle, Skeletal
  • Polymerase Chain Reaction
  • Protein Kinases