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Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities.

ALS2 is an autosomal recessive form of spastic paraparesis (motor neuron disease) with juvenile onset and slow progression caused by loss of function of alsin, an activator of Rac1 and Rab5 small GTPases. To establish an animal model of ALS2 and derive insights into the pathogenesis of this illness, we have generated alsin-null mice. Cytosol from brains of Als2(-/-) mice shows marked diminution of Rab5-dependent endosome fusion activity. Furthermore, primary neurons from Als2(-/-) mice show a disturbance in endosomal transport of insulin-like growth factor 1 (IGF1) and BDNF receptors, whereas neuronal viability and endocytosis of transferrin and dextran seem unaltered. There is a significant decrease in the size of cortical motor neurons, and Als2(-/-) mice are mildly hypoactive. Altered trophic receptor trafficking in neurons of Als2(-/-) mice may underlie the histopathological and behavioral changes observed and the pathogenesis of ALS2.

Pubmed ID: 16769894


  • Devon RS
  • Orban PC
  • Gerrow K
  • Barbieri MA
  • Schwab C
  • Cao LP
  • Helm JR
  • Bissada N
  • Cruz-Aguado R
  • Davidson TL
  • Witmer J
  • Metzler M
  • Lam CK
  • Tetzlaff W
  • Simpson EM
  • McCaffery JM
  • El-Husseini AE
  • Leavitt BR
  • Hayden MR


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

June 20, 2006

Associated Grants

  • Agency: NCRR NIH HHS, Id: S10 RR019409-01

Mesh Terms

  • Animals
  • Behavior, Animal
  • Body Weight
  • Cytosol
  • Endocytosis
  • Endosomes
  • Guanine Nucleotide Exchange Factors
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity
  • Motor Neurons
  • Motor Skills Disorders
  • Physical Conditioning, Animal
  • Protein Transport
  • Receptor, trkB
  • Time Factors