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Protective Role of rAAV-NDI1, Serotype 5, in an Acute MPTP Mouse Parkinson's Model
Jennifer Barber-Singh1, Byoung Boo Seo, Akemi Matsuno-Yagi
1Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, MEM256, La Jolla, CA 92037, USA.
Abstract:
Defects in mitochondrial proton-translocating NADH-quinone oxidoreductase (complex I) have been implicated in a number of acquired and hereditary diseases including Leigh's syndrome and more recently Parkinson's disease. A limited number of strategies have been attempted to repair the damaged complex I with little or no success. We have recently shown that the non-proton-pumping, internal NADH-ubiquinone oxidoreductase (Ndi1) from Saccharomyces cerevisiae (baker's yeast) can be successfully inserted into the mitochondria of mice and rats, and the enzyme was found to be fully active. Using recombinant adenoassociated virus vectors (serotype 5) carrying our NDI1 gene, we were able to express the Ndi1 protein in the substantia nigra (SN) of C57BL/6 mice with an expression period of two months. The results show that the AAV serotype 5 was highly efficient in expressing Ndi1 in the SN, when compared to a previous model using serotype 2, which led to nearly 100% protection when using an acute MPTP model. It is conceivable that the AAV-serotype5 carrying the NDI1 gene is a powerful tool for proof-of-concept study to demonstrate complex I defects as the causable factor in diseases of the brain.
Insights
Mitochondrial complex I defects are linked to neurological diseases. Introducing the yeast Ndi1 enzyme via AAV-serotype 5 successfully restored function in mouse models, offering a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Gene Therapy
Background:
- Mitochondrial NADH-quinone oxidoreductase (complex I) defects are implicated in neurodegenerative diseases like Parkinson's.
- Previous attempts to repair complex I have shown limited success.
- The non-proton-pumping Ndi1 enzyme from yeast has been shown to be active when introduced into mammalian mitochondria.
Purpose of the Study:
- To evaluate the efficacy of using recombinant adeno-associated virus serotype 5 (AAV5) to deliver the NDI1 gene into the substantia nigra (SN) of mice.
- To assess the potential of Ndi1 as a therapeutic agent for complex I-related neurological disorders.
Main Methods:
- Utilized AAV serotype 5 vectors carrying the NDI1 gene for delivery.
- Expressed the Ndi1 protein in the substantia nigra of C57BL/6 mice.
- Evaluated Ndi1 expression and efficacy using an acute MPTP mouse model.
Main Results:
- AAV serotype 5 demonstrated high efficiency in expressing Ndi1 in the mouse SN over a two-month period.
- Expression of Ndi1 led to nearly 100% protection in an acute MPTP model, indicating functional restoration.
- AAV5-mediated Ndi1 delivery proved more effective than previous AAV2-based approaches.
Conclusions:
- AAV5-mediated NDI1 gene transfer is a powerful tool for studying complex I defects in brain diseases.
- This approach shows promise as a proof-of-concept for treating conditions associated with complex I dysfunction.
- Restoring complex I activity via Ndi1 offers a potential therapeutic avenue for neurodegenerative diseases.
