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

Hideki Mochizuki, Hideki Hayakawa, Makoto Migita, Mamoru Shibata, Ryota Tanaka, Asuka Suzuki, Yumi Shimo-Nakanishi, Takao Urabe, Masanori Yamada, Kenji Tamayose, Takashi Shimada, Masayuki Miura, Yoshikuni Mizuno

Research output: Contribution to journalArticle

141 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)10918-10923
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number19
DOIs
Publication statusPublished - 2001 Sep 11

    Fingerprint

ASJC Scopus subject areas

  • General

Cite this

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. (2001). An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America, 98(19), 10918-10923. https://doi.org/10.1073/pnas.191107398