Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking.
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.
Hadano
Shinji
S
Department of Molecular Neuroscience, The Institute of Medical Sciences, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
Benn
Susanna C
SC
Kakuta
Shigeru
S
Otomo
Asako
A
Sudo
Katsuko
K
Kunita
Ryota
R
Suzuki-Utsunomiya
Kyoko
K
Mizumura
Hikaru
H
Shefner
Jeremy M
JM
Cox
Gregory A
GA
Iwakura
Yoichiro
Y
Brown
Robert H
RH
Ikeda
Joh-E
JE
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D015139:Blotting, Southern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics*; D017931:DNA Primers; D004594:Electrophysiology; D011992:Endosomes / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000473:pathology; D009422:Nervous System Diseases / Q000235:genetics*; D011689:Purkinje Cells / Q000473:pathology
C493235:ALS2CL protein, mouse; D002352:Carrier Proteins; D017931:DNA Primers; D020662:Guanine Nucleotide Exchange Factors; D004815:Epidermal Growth Factor