title: Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities.
abstract: 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.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, 980 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4.
authors.forename: R S
authors.initials: RS
authors.lastname: Devon
authors.forename: P C
authors.initials: PC
authors.lastname: Orban
authors.forename: K
authors.initials: K
authors.lastname: Gerrow
authors.forename: M A
authors.initials: MA
authors.lastname: Barbieri
authors.forename: C
authors.initials: C
authors.lastname: Schwab
authors.forename: L P
authors.initials: LP
authors.lastname: Cao
authors.forename: J R
authors.initials: JR
authors.lastname: Helm
authors.forename: N
authors.initials: N
authors.lastname: Bissada
authors.forename: R
authors.initials: R
authors.lastname: Cruz-Aguado
authors.forename: T-L
authors.initials: TL
authors.lastname: Davidson
authors.forename: J
authors.initials: J
authors.lastname: Witmer
authors.forename: M
authors.initials: M
authors.lastname: Metzler
authors.forename: C K
authors.initials: CK
authors.lastname: Lam
authors.forename: W
authors.initials: W
authors.lastname: Tetzlaff
authors.forename: E M
authors.initials: EM
authors.lastname: Simpson
authors.forename: J M
authors.initials: JM
authors.lastname: McCaffery
authors.forename: A E
authors.initials: AE
authors.lastname: El-Husseini
authors.forename: B R
authors.initials: BR
authors.lastname: Leavitt
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight; D003600:Cytosol / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism* / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology*; D019957:Motor Skills Disorders / Q000473:pathology* / Q000503:physiopathology*; D010805:Physical Conditioning, Animal; D021381:Protein Transport; D020813:Receptor, trkB / Q000378:metabolism; D013997:Time Factors
chemical_list: C512358:Als2 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D020813:Receptor, trkB