ArticleMolecular genetics and metabolism
An animal model of PDH deficiency using AAV8-siRNA vector-mediated knockdown of pyruvate dehydrogenase E1α.
Article in Molecular genetics and metabolism. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 19 citations in OpenAlex.
- Animal models of pyruvate dehydrogenase complex deficiency: insight into mechanisms of cerebral abnormalities and tissue-specific role in metabolism.Frontiers in medicine · 2026Review
- Review
- Re-routing Metabolism by the Mitochondrial Pyruvate Carrier Inhibitor MSDC-0160 Attenuates Neurodegeneration in a Rat Model of Parkinson's Disease.Molecular neurobiology · 2022Article
- Metabolic etiologies in West syndrome.Epilepsia open · 2018Review
- Efficient Gene Delivery and Expression in Pancreas and Pancreatic Tumors by Capsid-Optimized AAV8 Vectors.Human gene therapy methods · 2017Article
- Adropin acts in brain to inhibit water drinking: potential interaction with the orphan G protein-coupled receptor, GPR19.American journal of physiology. Regulatory, integrative and comparative physiology · 2016Article
- Site-Directed Mutagenesis of Surface-Exposed Lysine Residues Leads to Improved Transduction by AAV2, But Not AAV8, Vectors in Murine Hepatocytes In Vivo.Human gene therapy methods · 2015Article
- Targeting carbonic anhydrase IX activity and expression.Molecules (Basel, Switzerland) · 2015Review
- Evidence for an interaction of neuronostatin with the orphan G protein-coupled receptor, GPR107.American journal of physiology. Regulatory, integrative and comparative physiology · 2012Article
- Self-complementary adeno-associated viral vectors for gene therapy of hemophilia B: progress and challenges.Expert review of hematology · 2011Review
- High-efficiency transduction of liver cancer cells by recombinant adeno-associated virus serotype 3 vectors.Journal of visualized experiments : JoVE · 2011Article
- Human hepatocyte growth factor receptor is a cellular coreceptor for adeno-associated virus serotype 3.Human gene therapy · 2010Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
We evaluated the feasibility of self-complementary adeno-associated virus (scAAV) vector-mediated knockdown of the pyruvate dehydrogenase complex using small interfering RNAs directed against the E1α subunit gene (PDHA1). AAV serotype 8 was used to stereotaxically deliver scAAV8-si3-PDHA1-Enhanced Green Fluorescent Protein (knockdown) or scAAV8-EGFP (control) vectors into the right striatum and substantia nigra of rats. Rotational asymmetry was employed to quantify abnormal rotation following neurodegeneration in the nigrostriatal system. By 20weeks after surgery, the siRNA-injected rats exhibited higher contralateral rotation during the first 10min following amphetamine administration and lower 90-min total rotations (p≤0.05). Expression of PDC E1α, E1β and E2 subunits in striatum was decreased (p≤0.05) in the siRNA-injected striatum after 14weeks. By week 25, both PDC activity and expression of E1α were lower (p≤0.05) in siRNA-injected striata compared to controls. E1α expression was associated with PDC activity (R(2)=0.48; p=0.006) and modestly associated with counterclockwise rotation (R(2)=0.51;p=0.07). The use of tyrosine-mutant scAAV8 vectors resulted in ~17-fold increase in transduction efficiency of rat striatal neurons in vivo. We conclude that scAAV8-siRNA vector-mediated knockdown of PDC E1α in brain regions typically affected in humans with PDC deficiency results in a reproducible biochemical and clinical phenotype in rats that may be further enhanced with the use of tyrosine-mutant vectors.
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