An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease
Open Access
- 4 September 2001
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 98 (19), 10918-10923
- https://doi.org/10.1073/pnas.191107398
Abstract
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 Parkinson9s 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 Parkinson9s disease. The major mechanism of dopaminergic neuronal death triggered by MPTP seems to be the mitochondrial apoptotic pathway.Keywords
This publication has 33 references indexed in Scilit:
- An APAF-1·Cytochrome c Multimeric Complex Is a Functional Apoptosome That Activates Procaspase-9Journal of Biological Chemistry, 1999
- Transgenic mice expressing a dominant negative mutant interleukin-1β converting enzyme show resistance to MPTP neurotoxicityNeuroReport, 1999
- Glial pathology but absence of apoptotic nigral neurons in long‐standing Parkinson's diseaseMovement Disorders, 1998
- Induction of Apoptotic Program in Cell-Free Extracts: Requirement for dATP and Cytochrome cCell, 1996
- A New Strategy for Large-Scale Preparation of High-Titer Recombinant Adeno-Associated Virus Vectors by Using Packaging Cell Lines and Sulfonated Cellulose Column ChromatographyHuman Gene Therapy, 1996
- Role of mitochondria in the etiology and pathogenesis of Parkinson's diseaseBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1995
- Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brainNature Genetics, 1994
- Prevention of Vertebrate Neuronal Death by the crmA GeneScience, 1994
- Induction of apoptosis in fibroblasts by IL-1β-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3Cell, 1993
- Efficient selection for high-expression transfectants with a novel eukaryotic vectorGene, 1991