MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity.
Mutations in the parkin gene cause autosomal recessive familial Parkinson's disease (PD). Parkin-deficient mouse models fail to recapitulate nigrostriatal dopaminergic neurodegeneration as seen in PD, but produce deficits in dopaminergic neurotransmission and noradrenergic-dependent behavior. Since sporadic PD is thought to be caused by a combination of genetic susceptibilities and environmental factors, we hypothesized that neurotoxic insults from catecholaminergic toxins would render parkin knockout mice more vulnerable to neurodegeneration. Accordingly, we investigated the susceptibility of catecholaminergic neurons in parkin knockout mice to the potent dopaminergic and noradrenergic neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) respectively. We report that nigrostriatal dopaminergic neurons in parkin knockout mice do not show increased susceptibility to the parkinsonian neurotoxin, MPTP, in acute, subacute and chronic dose regimens of the neurotoxin. Additionally, parkin knockout mice do not show increased vulnerability to the noradrenergic neurotoxin, DSP-4, regarding levels of norepinephrine in cortex, brain stem and spinal cord. These findings suggest that absence of parkin in mice does not increase susceptibility to the loss of catecholaminergic neurons upon exposure to both dopaminergic and noradrenergic neurotoxins.
Thomas
Bobby
B
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
von Coelln
Rainer
R
Mandir
Allen S
AS
Trinkaus
Daniel B
DB
Farah
Mohamed H
MH
Leong Lim
Kah
K
Calingasan
Noel Y
NY
Flint Beal
M
M
Dawson
Valina L
VL
Dawson
Ted M
TM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001596:Benzylamines / Q000633:toxicity; D002395:Catecholamines / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D019610:Cytoprotection / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D009638:Norepinephrine / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D001596:Benzylamines; D002395:Catecholamines; D009498:Neurotoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C012102:DSP 4; D009638:Norepinephrine