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An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease.

Authors: Mochizuki, H  Hayakawa, H  Migita, M  Shibata, M  Tanaka, R  Suzuki, A  Shimo-Nakanishi, Y  Urabe, T  Yamada, M  Tamayose, K  Shimada, T  Miura, M  Mizuno, Y 
Citation: Mochizuki H, etal., Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10918-23. doi: 10.1073/pnas.191107398. Epub 2001 Sep 4.
Pubmed: (View Article at PubMed) PMID:11535810
DOI: Full-text: DOI:10.1073/pnas.191107398

Adeno-associated virus (AAV) vector delivery of an Apaf-1-dominant negative inhibitor was tested for its antiapoptotic effect on degenerating nigrostriatal neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. The wild-type caspase recruitment domain of Apaf-1 was used as a dominant negative inhibitor of Apaf-1 (rAAV-Apaf-1-DN-EGFP). An AAV virus vector was used to deliver it into the striatum of C57 black mice, and the animals were treated with MPTP. The number of tyrosine hydroxylase-positive neurons in the substantia nigra was not changed on the rAAV-Apaf-1-DN-EGFP injected side compared with the noninjected side. We also examined the effect of a caspase 1 C285G mutant as a dominant negative inhibitor of caspase 1 (rAAV-caspase-1-DN-EGFP) in the same model. However, there was no difference in the number of tyrosine hydroxylase-positive neurons between the rAAV-caspase-1-DN-EGFP injected side and the noninjected side. These results indicate that delivery of Apaf-1-DN by using an AAV vector system can prevent nigrostriatal degeneration in MPTP mice, suggesting that it could be a promising therapeutic strategy for patients with Parkinson's disease. The major mechanism of dopaminergic neuronal death triggered by MPTP seems to be the mitochondrial apoptotic pathway.

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CRRD ID: 13503334
Created: 2018-01-11
Species: All species
Last Modified: 2018-01-11
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.