Exp Mol Med.
2018 Feb;50(2):e440. 10.1038/emm.2017.261.
Protection of nigral dopaminergic neurons by AAV1 transduction with Rheb(S16H) against neurotoxic inflammation in vivo
- Affiliations
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- 1School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Korea. srk75@knu.ac.kr
- 2Department of Brain-Cognitive Science, Daegu-Gyeongbuk Institute of Science and Technology, Daegu, Korea.
- 3Predictive Model Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Daejeon, Korea.
- 4Department of Biochemistry and Molecular Biology, Department of Neuroscience Graduate School, School of Medicine, Kyung Hee University, Seoul, Korea.
- 5Department of Neurology, Columbia University, New York, NY, USA.
- 6Pathology and Cell Biology, Columbia University, New York, NY, USA.
- 7Department of Neural Development and Disease, Korea Brain Research Institute, Daegu, Korea.
- 8Department of Science in Korean Medicine, College of Korean Medicine, Seoul, Korea.
- 9KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Korea.
- 10Brain Science and Engineering Institute, Kyungpook National University, Daegu, Korea.
- KMID: 2440022
- DOI: http://doi.org/10.1038/emm.2017.261
Abstract
- We recently reported that adeno-associated virus serotype 1 (AAV1) transduction of murine nigral dopaminergic (DA) neurons with constitutively active ras homolog enriched in brain with a mutation of serine to histidine at position 16 [Rheb(S16H)] induced the production of neurotrophic factors, resulting in neuroprotective effects on the nigrostriatal DA system in animal models of Parkinson's disease (PD). To further investigate whether AAV1-Rheb(S16H) transduction has neuroprotective potential against neurotoxic inflammation, which is known to be a potential event related to PD pathogenesis, we examined the effects of Rheb(S16H) expression in nigral DA neurons under a neurotoxic inflammatory environment induced by the endogenous microglial activator prothrombin kringle-2 (pKr-2). Our observations showed that Rheb(S16H) transduction played a role in the neuroprotection of the nigrostriatal DA system against pKr-2-induced neurotoxic inflammation, even though there were similar levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β), in the AAV1-Rheb(S16H)-treated substantia nigra (SN) compared to the SN treated with pKr-2 alone; the neuroprotective effects may be mediated by the activation of neurotrophic signaling pathways following Rheb(S16H) transduction of nigral DA neurons. We conclude that AAV1-Rheb(S16H) transduction of neuronal populations to activate the production of neurotrophic factors and intracellular neurotrophic signaling pathways may offer promise for protecting adult neurons from extracellular neurotoxic inflammation.
MeSH Terms
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Adult
Brain
Cytokines
Dependovirus
Dopaminergic Neurons*
Histidine
Humans
Inflammation*
Models, Animal
Nerve Growth Factors
Neurons
Neuroprotection
Neuroprotective Agents
Prothrombin
Serine
Serogroup
Substantia Nigra
Tumor Necrosis Factor-alpha
Cytokines
Histidine
Nerve Growth Factors
Neuroprotective Agents
Prothrombin
Serine
Tumor Necrosis Factor-alpha
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