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FeLV envelope protein (gp70) variable region 5 causes alterations in calcium homeostasis and toxicity of neurons
T W Mitchell1, J L Rojko, J R Hartke
1Department of Anatomy and Neurobiology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins 80523, USA.
Abstract:
In humans and animals, retroviruses have been implicated in nervous system disease. Our objective was to characterize the neurotoxicity of a peptide sequence derived from an animal retrovirus, the feline leukemia virus (FeLV). Using a peptide sequence from the subtype FeLV-C envelope protein variable region 5 (VR5), cytotoxicity was demonstrated in studies that evaluated neuronal survival, neurite outgrowth, and alterations in intracellular calcium ion concentration. The FeLV subtype isolate FeLV-CSarma possesses an envelope protein VR5 amino acid sequence that varies by four amino acids from the VR5 amino acid sequence of subtype FeLV-AGlasgow. The polypeptide representing the VR5 of FeLV-CSarma (FeLV-CVR5) is significantly more neurotoxic than the polypeptide sequence representing the VR5 of FeLV-AGlasgow (FeLV-AVR5). FeLV-CVR5 (> or = 3 microM) exposure resulted in significant dose-dependent neurotoxicity. Antibodies to FeLV-CVR5 blocked this effect. Neurite outgrowth was significantly reduced at all tested concentrations (3-12 microM) of FeLV-CVR5, with a 92% reduction in neurite length at 12 microM. FeLV-AVR5 was significantly less neurotoxic with respect to neurite outgrowth than was FeLV-CVR5. The significant reduction in neurotoxicity for FeLV-AVR5 illustrates the importance of the 4-amino-acid difference between it and FeLV-CVR5. Alterations in intracellular calcium ion concentration were associated with this neurotoxicity.
Insights
A feline leukemia virus (FeLV) peptide, FeLV-CVR5, causes significant neurotoxicity by altering calcium levels. Antibodies targeting FeLV-CVR5 can block this effect, highlighting specific viral sequences
Area of Science:
- Neurovirology
- Molecular Biology
Background:
- Retroviruses are linked to nervous system diseases in humans and animals.
- Feline leukemia virus (FeLV) is an animal retrovirus with potential neurotoxic implications.
Purpose of the Study:
- To characterize the neurotoxicity of a specific peptide sequence from the FeLV envelope protein, variable region 5 (VR5).
- To compare the neurotoxicity of FeLV-CVR5 (from FeLV-CSarma) with FeLV-AVR5 (from FeLV-AGlasgow).
Main Methods:
- In vitro studies evaluating neuronal survival, neurite outgrowth, and intracellular calcium ion concentration.
- Peptide exposure assays using FeLV-CVR5 and FeLV-AVR5 at varying concentrations (3-12 microM).
- Immunological blocking assays using antibodies against FeLV-CVR5.
Main Results:
- FeLV-CVR5 demonstrated significant dose-dependent neurotoxicity, reducing neurite outgrowth by 92% at 12 microM.
- FeLV-AVR5 exhibited significantly less neurotoxicity compared to FeLV-CVR5, underscoring the impact of a 4-amino-acid difference.
- Neurotoxicity was associated with alterations in intracellular calcium ion concentration.
- Antibodies targeting FeLV-CVR5 effectively blocked the observed neurotoxic effects.
Conclusions:
- The FeLV-CVR5 peptide is a potent neurotoxin, with its toxicity modulated by specific amino acid variations.
- Intracellular calcium dysregulation is a key mechanism in FeLV-induced neurotoxicity.
- Targeting specific viral peptide sequences, like FeLV-CVR5, may offer therapeutic avenues for retroviral nervous system diseases.