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Current Neuropharmacology

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ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

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Research Article

Overexpression of mTOR in Leukocytes from ALS8 Patients

Author(s): Nathália Augusta Gomes, Francisco das Chagas Lima e Silva, Caroline Maria de Oliveira Volpe, Pedro Henrique Villar-Delfino, Camila Ferreira de Sousa, Fabiana Rocha-Silva and José Augusto Nogueira-Machado*

Volume 21, Issue 3, 2023

Published on: 07 February, 2023

Page: [482 - 490] Pages: 9

DOI: 10.2174/1570159X21666230201151016

Price: $65

Abstract

Background: The mutated VAPBP56S (vesicle B associated membrane protein – P56S) protein has been described in a Brazilian family and classified as Amyotrophic Lateral Sclerosis type 8 (ALS8).

Objective: We aimed to study altered biochemical and immunological parameters in cells from ALS8 patients to identify possible biomarkers or therapeutic targets.

Methods: Wild-type VAPB, VAPBP56S, mTOR, proinflammatory cytokines, and oxidant/reducing levels in serum, leucocytes, and cellular lysate from ALS8 patients and health Controls were performed by ELISA, fluorimetry, and spectrophotometry.

Results: Our results showed similar levels of mutant and wild-type VAPB in serum and intracellular lysate (p > 0.05) when ALS8 patients and Controls were compared. IL-1β, IL-6, and IL-18 levels in patients and Controls showed no difference, suggesting an absence of peripheral inflammation (p > 0.05). Oxidative metabolic response, assessed by mitochondrial ROS production, and reductive response by MTT reduction, were higher in the ALS8 group compared to Controls (p < 0.05), although not characterizing typical oxidative stress in ALS8 patients. Total mTOR levels (phosphorylated or non-phosphorylated) of ALS8 patients were significantly lower in serum and higher in intracellular lysate than the mean equivalents in Controls (p < 0.05). A similar result was observed when we quantified the phosphorylated protein (p < 0.05).

Conclusion: We demonstrate the possibility of using these biochemical and immunological parameters as potential therapeutic targets or biomarkers. Furthermore, by hypothesis, we suggest a hormetic response in which both VAPB forms could coexist in different proportions throughout life. The mutated VAPBP56S production would increase with aging and predominate over the wild-type VAPB levels, determining the onset of symptoms and aggravating the disease.

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