Radical changes in multiple sclerosis pathogenesis

Horssen, Jack van; Witte, Maarten E.; Schreibelt, Gerty; Vries, Helga E. de

doi:10.1016/j.bbadis.2010.06.011

Cited by 274 publications

(206 citation statements)

References 135 publications

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Section: Autophagy and Mitochondria In Msmentioning

confidence: 99%

“…In MS, the decreased expression of cytochrome c oxidase subunit 5b may impair the function of mitochondria [24] . Dysfunction of mitochondria produces reactive oxygen species (ROS), which contribute to demyelination and axonal loss [25] .Autophagy clears depolarized mitochondria to reduce the excessive production of ROS by increasing BECN1 or regulating ATG4 activity [26,27] , which is protective in MS. …”

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confidence: 99%

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Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

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Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively infl uences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Infl ammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-infl ammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinfl ammation associated with the pathogenesis of MS. Keywords: autophagy; multiple sclerosis; neuro-infl ammation ·Review· IntroductionAutophagy, a lysosome-dependent degradation pathway, contributes to maintaining cellular homeostasis. Clearance of long-lived proteins, unnecessary organelles, and aggregate-prone proteins is mainly executed by autophagy for recycling cellular materials [1] . There are three subtypes of autophagy, macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy. Macroautophagy is the major type for selective degradation of protein aggregates or misfolded proteins. The ubiquitin-labeled proteins are recognized by autophagy receptors, such as p62, neighbor of BRCA1 gene 1 (NBR1), and NIP3-like protein X (NIX), to form autophagosomes that then fuse with lysosomes for degradation. Many autophagy-related genes function during this process, such as Unc51-like kinase (ULK1) and autophagy-related gene (ATG) 5. Mammalian target of rapamycin (mTOR) represses autophagy by regulating ULK1 phosphorylation, while AMPK activates this process.CMA mediates the degradation of large molecular-weight proteins containing the KFERQ motif recognized by heat shock cognate protein of 70 kDa (HSC70). The substrate is then escorted to lysosome-associated membrane protein 2 (LAMP2A) for lysosomal degradation. Mitophagy is responsible for the degradation of damaged mitochondria.Parkin and PINK1 play critical roles in this process [2] . More Neurosci Bull August 1, 2015, 31(4): 435-444 436 attention has been paid to autophagy in the path...

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Section: Autophagy and Mitochondria In Msmentioning

confidence: 99%

mentioning

confidence: 99%

Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

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“…A major role for reactive oxygen species (ROS) in the pathophysiology of MS and central nervous system (CNS) inflammatory disorders has been demonstrated (Cross et al, 1998;Smith et al, 1999;van Horssen et al, 2011). An imbalance in cellular redox homeostasis, leading to oxidative stress, may be caused by a large number of biological mechanisms resulting in the overproduction of ROS (Murphy, 2009).…”

Section: Introductionmentioning

confidence: 99%

Oxidative injury in multiple sclerosis cerebellar grey matter

et al. 2016

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. AbstractCerebellar dysfunction is a significant contributor to disability in multiple sclerosis (MS). Both white matter (WM) and grey matter (GM) injury occurs within MS cerebellum and, within GM, demyelination, inflammatory cell infiltration and neuronal injury contribute to on-going pathology. The precise nature of cerebellar GM injury is, however, unknown. Oxidative stress pathways with ultimate lipid peroxidation and cell membrane injury occur extensively in MS and the purpose of this study was to investigate these processes in MS cerebellar GM. Post-mortem human cerebellar GM from MS and control subjects was analysed immunohistochemically, followed by semi-quantitative analysis of markers of cellular injury, lipid peroxidation and antioxidant enzyme expression. We have shown evidence for reduction in myelin and neuronal markers in MS GM, coupled to an increase in expression of a microglial marker. We also show that the lipid peroxidation product 4-hydroxynonenal co-localises with myelin and its levels negatively correlate to myelin basic protein levels. Furthermore, superoxide dismutase (SOD1 and 2) enzymes, localised within cerebellar neurons, are up-regulated, yet the activation of subsequent enzymes responsible for the detoxification of hydrogen peroxide, catalase and glutathione peroxidase are relatively deficient. These studies provide evidence for oxidative injury in MS cerebellar GM and further help define disease mechanisms within the MS brain.

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“…2 Oxidative stress and antioxidant mechanisms in MS ROS are highly reactive molecules that play important roles in various physiological cellular processes, such as cell signaling, gene expression and host defense; however, increased ROS levels induce oxidative stress, which is a common pathological feature in several neurological disorders, including MS. 2,3 To protect themselves from ROS-induced damage and cell death, cells are equipped with an elaborate antioxidant machinery and under physiological conditions, the levels of cellular ROS are in equilibrium with this endogenous antioxidant system; however, when this balance is altered by either an increase in ROS production or reduced antioxidant protection, oxidative stress and subsequent damage to proteins, lipids and deoxyribonucleic acid (DNA) occurs. 2,3 The CNS is particularly sensitive to oxidative stress, due to its high cellular metabolic activity and enrichment in polyunsaturated fatty acids. 4 Furthermore, the activities of antioxidant enzymes, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) are reported to be lower in the brain, compared to other tissues.…”

Section: Introductionmentioning

confidence: 99%

“…4 Altogether, this suggests that detoxification and antioxidant protection against ROS are essential processes within the brain, and many reports underscore the importance of oxidative stress in MS pathogenesis. 2,[5][6][7] Sources of ROS in MS: Activated macrophages and microglia, and mitochondrial dysfunction Two different sources are mainly responsible for ROS production within the cell: ROS-producing enzymes and mitochondria. ROS-producing enzymes are highly expressed in macrophages, neutrophils and microglia, in order to kill invading pathogens in a process called oxidative burst.…”

Section: Introductionmentioning

confidence: 99%

Glutathione in multiple sclerosis: More than just an antioxidant?

et al. 2014

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Abstract:Oxidative stress has been strongly implicated in both the inflammatory and neurodegenerative pathological mechanisms in multiple sclerosis (MS). In response to oxidative stress, cells increase and activate their cellular antioxidant mechanisms. Glutathione (GSH) is the major antioxidant in the brain, and as such plays a pivotal role in the detoxification of reactive oxidants. Previous research has shown that GSH homeostasis is altered in MS. In this review, we provide a comprehensive overview on GSH metabolism in brain cells, with a focus on its involvement in MS. The potential of GSH as an in vivo biomarker in MS is discussed, along with a short overview of improvements in imaging methods that allow non-invasive quantification of GSH in the brain. These methods might be instrumental in providing realtime measures of GSH, allowing the assessment of the oxidative state in MS patients and the monitoring of disease progression. Finally, the therapeutic potential of GSH in MS is discussed.

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Radical changes in multiple sclerosis pathogenesis

Cited by 274 publications

References 135 publications

Role of autophagy in the pathogenesis of multiple sclerosis

Role of autophagy in the pathogenesis of multiple sclerosis

Oxidative injury in multiple sclerosis cerebellar grey matter

Glutathione in multiple sclerosis: More than just an antioxidant?

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