Correlation between auto/mitophagic processes and magnetic resonance imaging activity in multiple sclerosis patients

Massimiliano Castellazzi,Ilaria Casetta,Paolo Pinton,Massimo Bonora,Carlotta Giorgi,Enrico Granieri,Mariapina Donadio,Maura Pugliatti,Enrico Fainardi,Simone Patergnani

doi:10.1186/s12974-019-1526-0

Massimiliano Castellazzi, Ilaria Casetta + Show 8 more

Open Access

https://doi.org/10.1186/s12974-019-1526-0

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Abstract

BackgroundAn alteration of autophagy and mitophagy, two highly conserved lysosome-dependent degradation pathways involved in the maintenance of cellular homeostasis, has been associated with multiple sclerosis (MS).ObjectiveTo search the level of autophagy-related 5 (ATG5) and Parkin proteins, as markers of autophagy and mitophagy respectively, and lactate in a cohort of MS patients.MethodsCerebrospinal fluid (CSF) and serum samples from 60 MS patients were analyzed: 30 with magnetic resonance imaging (MRI) evidence of disease activity, gadolinium (Gd)-based contrast agent positive (Gd+), and 30 without MRI evidence of disease activity (Gd−). ATG5, Parkin, and lactate were measured using commercially available products.Results and conclusionsSerum levels of ATG5, Parkin, and lactate were more elevated in Gd+ than in Gd− MS patients (p < 0.0001), and CSF concentrations of ATG5 and Parkin were greater in Gd+ than in Gd− MS (p < 0.0001). Our results demonstrated that molecular markers of autophagy and mitophagy are increased in CSF of MS patients during the active phases of the disease and that these catabolic markers, together with lactate, are also remarkably augmented in blood suggesting a role of these processes in MS pathogenesis and the possible use of these molecules as biomarkers of disease activity.

Highlights

Autophagy, a lysosome-dependent degradation pathway, is a highly conserved complex cellular mechanism involved in the maintenance of cellular homeostasis through the degradation of senescent subcellular organelles, infectious agents, and misfolded proteins [1].Increasing evidence indicates that autophagy is involved in various physiological processes and in the pathogenesis of complex diseases, such as autoimmuneCastellazzi et al Journal of Neuroinflammation (2019) 16:131 has shown therapeutic effects in the animal model of multiple sclerosis (MS) [10].A selective form of autophagy is involved in the elimination of damaged mitochondria in a process called mitophagy [11]
We proved that molecular markers of autophagy and mitophagy were elevated in the central nervous system (CNS) of MS patients compared to neurological controls, suggesting a role of these two mechanisms in the pathogenesis and/or development of MS [21]
If on the one hand it is accepted that the reduction of autophagy and mitophagy processes within the CNS is mainly related to neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease [17], on the other hand, our studies show that an increase of soluble markers of these two metabolic processes is related to the presence of a chronic CNS inflammation and that these markers further increase during the acute phase of the inflammatory reaction

Summary

Introduction

A lysosome-dependent degradation pathway, is a highly conserved complex cellular mechanism involved in the maintenance of cellular homeostasis through the degradation of senescent subcellular organelles, infectious agents, and misfolded proteins [1].Increasing evidence indicates that autophagy is involved in various physiological processes and in the pathogenesis of complex diseases, such as autoimmuneCastellazzi et al Journal of Neuroinflammation (2019) 16:131 has shown therapeutic effects in the animal model of MS [10].A selective form of autophagy is involved in the elimination of damaged mitochondria in a process called mitophagy [11]. A lysosome-dependent degradation pathway, is a highly conserved complex cellular mechanism involved in the maintenance of cellular homeostasis through the degradation of senescent subcellular organelles, infectious agents, and misfolded proteins [1]. Suppression of mitophagy leads to accumulation of aberrant mitochondria, reactive oxygen species (ROS) overload, and consequent mitochondrial malfunction [12]. Impairments in the correct functioning of the mitochondrial population can lead to activation of inflammatory signaling pathways [15] with the consequent establishment of a chronic inflammatory condition that could result in the development of autoimmune diseases [16]. An alteration of autophagy and mitophagy, two highly conserved lysosome-dependent degradation pathways involved in the maintenance of cellular homeostasis, has been associated with multiple sclerosis (MS)

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