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Human Molecular Genetics Advance Access originally published online on December 1, 2005
Human Molecular Genetics 2006 15(2):233-250; doi:10.1093/hmg/ddi440
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking

Shinji Hadano1,2,3,{dagger}, Susanna C. Benn4,{dagger}, Shigeru Kakuta5, Asako Otomo1, Katsuko Sudo5,{ddagger}, Ryota Kunita1,3, Kyoko Suzuki-Utsunomiya1, Hikaru Mizumura3, Jeremy M. Shefner6, Gregory A. Cox7, Yoichiro Iwakura5, Robert H. Brown, Jr4 and Joh-E Ikeda1,2,3,8,*

1Department of Molecular Neuroscience, The Institute of Medical Sciences and 2Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan, 3Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, 4Day Neuromuscular Research Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA, 5Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, 6Department of Neurology, SUNY Upstate Medical University, Syracuse, NY 13104, USA, 7The Jackson Laboratory, Bar Harbor, ME 04609, USA and 8Department of Paediatrics, Faculty of Medicine, University of Ottawa, Ontario, Canada K1H 8M5

* To whom correspondence should be addressed. Tel: +81 463915095; Fax: +81 463914993; Email: joh-e{at}nga.med.u-tokai.ac.jp

Received September 27, 2005; Accepted November 25, 2005

ALS2/alsin is a member of guanine nucleotide exchange factors for the small GTPase Rab5 (Rab5GEFs), which act as modulators in endocytic pathway. Loss-of-function mutations in human ALS2 account for a number of juvenile recessive motor neuron diseases (MNDs). However, the normal physiological role of ALS2 in vivo and the molecular mechanisms underlying motor dysfunction are still unknown. To address these issues, we have generated mice homozygous for disruption of the Als2 gene. The Als2-null mice observed through 21 months of age demonstrated no obvious developmental, reproductive or motor abnormalities. However, immunohistochemical and electrophysiological analyses identified an age-dependent, slowly progressive loss of cerebellar Purkinje cells and disturbance of spinal motor neurons associated with astrocytosis and microglial cell activation, indicating a subclinical dysfunction of motor system in Als2-null mice. Further, quantitative epidermal growth factor (EGF)-uptake analysis identified significantly smaller-sized EGF-positive endosomes in Als2-null fibroblasts, suggesting an alteration of endosome/vesicle trafficking in the cells. Collectively, while loss of ALS2 does not produce a severe disease phenotype in mice, these Als2-null animals should provide a useful model with which to understand the interplay between endosomal dynamics and the long-term viability of large neurons such as Purkinje cells and spinal motor neurons.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

{ddagger} Present address: Animal Research Center, Tokyo Medical University, Tokyo 160-8402, Japan.


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