Oxidative stress is responsible for deficient survival and dendritogenesis in purkinje neurons from ataxia-telangiectasia mutated mutant mice.
Atm gene-disrupted mice recapitulate the majority of characteristics observed in patients with the genetic disorder ataxia-telangiectasia (A-T). However, although they exhibit defects in neuromotor function and a distinct neurological phenotype, they do not show the progressive neurodegeneration seen in human patients, but there is evidence that ataxia-telangiectasia mutated (Atm)-deficient animals have elevated levels of oxidized macromolecules and some neuropathology. We report here that in vitro survival of cerebellar Purkinje cells from both Atm "knock-out" and Atm "knock-in" mice was significantly reduced compared with their wild-type littermates. Although most of the Purkinje neurons from wild-type mice exhibited extensive dendritic elongation and branching under these conditions, most neurons from Atm-deficient mice had dramatically reduced dendritic branching. An antioxidant (isoindoline nitroxide) prevented Purkinje cell death in Atm-deficient mice and enhanced dendritogenesis to wild-type levels. Furthermore, administration of the antioxidant throughout pregnancy had a small enhancing effect on Purkinje neuron survival in Atm gene-disrupted animals and protected against oxidative stress in older animals. These data provide strong evidence for a defect in the cerebellum of Atm-deficient mice and suggest that oxidative stress contributes to this phenotype.
Chen
Philip
P
The Queensland Institute of Medical Research, Royal Brisbane Hospital, Herston, Queensland 4029, Australia.
Peng
Cheng
C
Luff
John
J
Spring
Kevin
K
Watters
Dianne
D
Bottle
Steven
S
Furuya
Shigeki
S
Lavin
Martin F
MF
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D016923:Cell Death; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D003712:Dendrites / Q000648:ultrastructure*; D005260:Female; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009589:Nitrogen Oxides / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011689:Purkinje Cells / Q000166:cytology* / Q000187:drug effects; D025521:Tumor Suppressor Proteins
C480578:5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl; D000975:Antioxidants; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007211:Indoles; D009589:Nitrogen Oxides; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C039900:nitroxyl