Progressive sensorimotor impairment is not associated with reduced dopamine and high energy phosphate donors in a model of ataxia-telangiectasia.
Ataxia-telangiectasia (A-T) is a genetic disease, associated with progressive motor impairment and a lack of functional ATM protein. It has been reported that immunoreactive tyrosine hydroxylase and dopamine transporter are reduced in an Atm-/- mouse model of A-T. These observations led to a hypothesis that A-T is associated with loss of nigrostriatal dopamine and prompted the launch of clinical trials to evaluate a therapeutic utility of the anti-parkinsonian drug, l-DOPA. To test for dopamine depletion more directly, we measured regional levels of monoamines and their metabolites in the Atm-/- mouse brain. We also measured levels of NAD+, a cofactor for dopamine biosynthesis and substrate of the DNA damage surveillance enzyme, poly(ADP-ribose) polymerase (PARP). Constitutive activation of PARP has been posited to cause NAD+ depletion. We observed no reduction in monoamine transmitters and no depletion of NAD+, or other high energy phosphate donors in the adult Atm-/- cerebellum, striatum, or ventral mesencephalon. However, our studies did reveal a progressive sensorimotor impairment in Atm-/- mice that may serve as a relevant proxy for progressive neurological impairment in the human disease. Our results call into question the involvement of dopamine in A-T and the therapeutic strategy of enhancing dopaminergic function with l-DOPA.
Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Ontario, Canada. howard.mount@utoronto.ca
Howard T J
HT
Mount
Jean-Claude
JC
Martel
Paul
P
Fluit
Yingji
Y
Wu
Eleanor
E
Gallo-Hendrikx
Cristina
C
Cosi
Marc R
MR
Marien
D000244:Adenosine Diphosphate / Q000032:analysis / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000032:analysis / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D064007:Ataxia Telangiectasia Mutated Proteins; D001522:Behavior, Animal / Q000502:physiology; D015306:Biogenic Monoamines / Q000032:analysis / Q000378:metabolism; D001923:Brain Chemistry; D002395:Catecholamines / Q000032:analysis / Q000378:metabolism; D018797:Cell Cycle Proteins; D002531:Cerebellum / Q000737:chemistry / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism*; D008636:Mesencephalon / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009243:NAD / Q000032:analysis / Q000378:metabolism*; D009249:NADP / Q000032:analysis / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D011597:Psychomotor Performance / Q000502:physiology; D012737:Sex Factors; D025521:Tumor Suppressor Proteins
D015306:Biogenic Monoamines; D002395:Catecholamines; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D009243:NAD; D000249:Adenosine Monophosphate; D009249:NADP; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C001746:3-methoxytyramine; D004298:Dopamine