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Neighbor effects of neurons bearing protective transgenes.

ABSTRACT: Viral vectors bearing protective transgenes can decrease neurotoxicity after varied necrotic insults. A neuron that dies necrotically releases glutamate, calcium and reactive oxygen species, thereby potentially damaging neighboring neurons. This raises the possibility that preventing such neuron death via gene therapy can secondarily protect neighboring neurons that, themselves, do not express a protective transgene. We determined whether such "good neighbor" effects occur, by characterizing neurons that, while uninfected themselves, are in close proximity to a transgene-bearing neuron. We tested two genes whose overexpression protects against excitotoxicity: anti-apoptotic Bcl-2, and a calcium-activated K(+) channel, SK2. Using herpes simplex virus type 2-mediated transgene delivery to hippocampal cultures, we observed "good neighbor" effects on neuronal survival following an excitotoxic insult. However, in the absence of insult, "bad neighbor" effects could also occur (i.e., where being in proximity to a neuron constitutively expressing one of those transgenes is deleterious). We also characterized the necessity for cell-cell contact for these effects. These phenomena may have broad implications for the efficacy of gene overexpression strategies in the CNS.

SUBMITTER: Lee AL

PROVIDER: S-EPMC2885846 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Neighbor effects of neurons bearing protective transgenes.

Lee Angela L AL Campbell Laura B LB Sapolsky Robert M RM

Brain research 20100424

Viral vectors bearing protective transgenes can decrease neurotoxicity after varied necrotic insults. A neuron that dies necrotically releases glutamate, calcium and reactive oxygen species, thereby potentially damaging neighboring neurons. This raises the possibility that preventing such neuron death via gene therapy can secondarily protect neighboring neurons that, themselves, do not express a protective transgene. We determined whether such "good neighbor" effects occur, by characterizing neu ...[more]

PMID: 20417625

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Project description:Quantifying interactions in DNA microarrays is of central importance for a better understanding of their functioning. Hybridization thermodynamics for nucleic acid strands in aqueous solution can be described by the so-called nearest-neighbor model, which estimates the hybridization free energy of a given sequence as a sum of dinucleotide terms. Compared with its solution counterparts, hybridization in DNA microarrays may be hindered due to the presence of a solid surface and of a high density of DNA strands. We present here a study aimed at the determination of hybridization free energies in DNA microarrays. Experiments are performed on custom Agilent slides. The solution contains a single oligonucleotide. The microarray contains spots with a perfect matching complementary sequence and other spots with one or two mismatches: in total 1006 different probe spots, each replicated 15 times per microarray. The free energy parameters are directly fitted from microarray data. The experiments demonstrate a clear correlation between hybridization free energies in the microarray and in solution. The experiments are fully consistent with the Langmuir model at low intensities, but show a clear deviation at intermediate (non-saturating) intensities. These results provide new interesting insights for the quantification of molecular interactions in DNA microarrays. Keywords: experiment to assess technical aspects of hybridization in microarrays The study consists of four experiments. Each experiments consists of one slide with eight identical microarrays which were hybridized with an identical solution but at a different concentration. Per experiment a single target sequence in solution was used for hybridization: target1 to target4 (Table 1 main manuscript or description of samples below). Each target oligo was bought in duplicate, referred to as oligos a and b. In experiment 1 and 2 a fragmentation step (f) was applied. More details can be found in the main manuscript especially Table 3.

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Neighbor effects of neurons bearing protective transgenes.

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Neighbor effects of neurons bearing protective transgenes.

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