title: A knockout of the caspase 2 gene produces increased resistance of the nigrostriatal dopaminergic pathway to MPTP-induced toxicity.
abstract: This study investigated the effect of a knockout of the caspase 2 gene on the sensitivity of murine nigral dopaminergic neurons to 1-methyl-4-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity. Female wild type (WT), heterozygous caspase 2 NL (HET) and homozygous caspase 2 null (NL) mice were treated with cumulative dosages of 0, 10, 15 or 20 mg/kg MPTP free base. Without MPTP treatment, one week later dopamine (DA) levels were not significantly different in HET or NL versus WT mice. Twenty mg/kg MPTP reduced striatal DA in WT and HET (p<0.01) but not NL mice. This same MPTP dosage regimen also induced a significantly greater decrease in tyrosine hydroxylase immunopositive (TH+) protein in striata of WT compared to NL mice (p<0.001). Subsequently, WT and NL mice were treated daily with 20 mg/kg MPTP for 3 days and 25 mg/kg MPTP for 2 additional days, and TH+ neurons in the substantia nigra (SN) were estimated using unbiased stereology. When compared to untreated WT, the numbers of TH+ neurons were significantly lower in the SN of untreated NL mice (p<0.05). Treatment with the MPTP regimen significantly reduced TH+ neurons in WT mice but not NL mice. In primary mesencephalic cultures both the cell bodies and the neuronal processes of TH immunopositive (TH+) neurons from NL embryos were significantly (p<0.001) more resistant to 10 μM MPP+ compared to WT. Following MPP+ treatment, features of apoptotic cell death were also significantly (p<0.001) more prevalent in nuclei of TH+ neurons in cultures prepared from WT versus NL mouse pups. These results suggest that caspase 2 may play a role in modulating the MPTP-induced damage to the nigrostriatal dopaminergic system.
authors.affiliation: The Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Tiwari
authors.forename: Brian
authors.initials: B
authors.lastname: Herman
authors.forename: William W
authors.initials: WW
authors.lastname: Morgan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D053143:Caspase 2 / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism*
chemical_list: D053143:Caspase 2; D004298:Dopamine