Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration.
Evidence garnered from both human autopsy studies and genetic animal models has suggested a potential role for astrocytes in the pathogenesis of amyotrophic lateral sclerosis (ALS). Currently, mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) represent the only known cause of motoneuron loss in the disease, producing 21q linked familial ALS (FALS). To determine whether astrocytic dysfunction has a primary role in familial ALS, we have generated multiple lines of transgenic mice expressing G86R mutant SOD1 restricted to astrocytes. In GFAP-m SOD1 mice, astrocytes exhibit significant hypertrophy and increased GFAP reactivity as the animals mature. However, GFAP-mutant SOD1 transgenic mice develop normally and do not experience spontaneous motor deficits with increasing age. Histological examination of spinal cord in aged GFAP-mSOD1 mice reveals normal motoneuron and microglial morphology. These results indicate that 21q linked FALS is not a primary disorder of astrocytes, and that expression of mutant SOD1 restricted to astrocytes is not sufficient to cause motoneuron degeneration in vivo. Expression of mutant SOD1 in other cell types, most likely neurons, is critical for the initiation of disease.
Gong
Y H
YH
Department of Neurology, University of Texas, Southwestern Medical Center, Dallas, Texas 75235, USA.
Parsadanian
A S
AS
Andreeva
A
A
Snider
W D
WD
Elliott
J L
JL
D000375:Aging; D019943:Amino Acid Substitution; D000818:Animals; D001253:Astrocytes / Q000201:enzymology* / Q000473:pathology / Q000502:physiology; D002891:Chromosomes, Human, Pair 21; D005260:Female; D005684:Gait; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D016472:Motor Neuron Disease / Q000235:genetics; D009046:Motor Neurons / Q000166:cytology* / Q000502:physiology; D017354:Point Mutation; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013116:Spinal Cord / Q000201:enzymology* / Q000473:pathology / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D011993:Recombinant Fusion Proteins; D013482:Superoxide Dismutase