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.
Highlights
To clarify that the therapeutic potential of neurotrophic factors for Parkinson’s disease (PD) depends on the sustained delivery of the appropriate amount to the target areas, we recently reported that adenoassociated virus 1 (AAV1) transduction of nigral DA neurons with a gene encoding the constitutively active form of ras homolog enriched in brain (Rheb) with a mutation of serine to histidine at position 16 [Rheb(S16H)] induced a sustained production of neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), through activation of the mammalian target of rapamycin complex 1, resulting in the protection and restoration of the nigrostriatal DA projection in neurotoxin-treated animal models of PD.[15,16,18,19]
associated virus serotype 1 (AAV1) transduction with Rheb(S16H) in the substantia nigra (SN) in vivo Mice were killed at 3 weeks after an intranigral injection of AAV1-green fluorescence protein (GFP) or AAV1-Rheb(S16H) to examine the viral transduction of nigral DA neurons, and the expression of target proteins was confirmed by observation of GFP expression and immunohistochemical staining for the FLAG epitope encoded in the Rheb(S16H) construct, respectively (Figure 1a and b)
Consistent with our previous results,[15,16,18] the doubleimmunofluorescence staining showed that GFP and FLAG were colocalized within tyrosine hydroxylase (TH)-positive neurons (Figure 1b) but not glial cells (GFAP-positive astrocytes and ionized calcium-binding adapter molecule 1 (Iba1)-positive microglia) (Figure 1c)
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by the loss of nigral dopaminergic (DA) neurons and a significant decrease in striatal dopamine levels.[1,2] numerous types of drugs can temporarily relieve PD symptoms, there is no comprehensive therapy for PD, and its pathogenic mechanism is largely unknown.[3,4] neurotoxic inflammation is considered to be an important mechanism in the pathogenesis of PD, and accumulating evidence indicates that activated microgliamediated neurotoxic inflammation can exacerbate the loss of DA neurons and deteriorate the symptoms of the disease, suggesting that the control of activated microglia may be a useful strategy for neuroprotection in the adult brain.[5,6,7,8,9]. Express decreased levels of glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor-β family, and brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family.[10] Experimental results using GDNF11–13 and BDNF11,14 have consistently shown their. Correspondence: Professor SR Kim, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea.
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