Rab32 connects ER stress to mitochondrial defects in multiple sclerosis.

Endoplasmic reticulum (ER) stress is a hallmark of neurodegenerative diseases such as multiple sclerosis (MS). However, this physiological mechanism has multiple manifestations that range from impaired clearance of unfolded proteins to altered mitochondrial dynamics and apoptosis. While connections between the triggering of the unfolded protein response (UPR) and downstream mitochondrial dysfunction are poorly understood, the membranous contacts between the ER and mitochondria, called the mitochondria-associated membrane (MAM), could provide a functional link between these two mechanisms. Therefore, we investigated whether the guanosine triphosphatase (GTPase) Rab32, a known regulator of the MAM, mitochondrial dynamics, and apoptosis, could be associated with ER stress as well as mitochondrial dysfunction.This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site

Mitochondrial Dysfunction in Multiple Sclerosis: A Systematic Review

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) and is characterized by a high degree of heterogeneity in progression and treatment response. Mitochondrial dysfunction is increasingly recognized as an important feature of MS pathology and may be relevant for clinical disease progression. This paper systematically reviews published evidence concerning the role of mitochondrial abnormalities with MS. Literature searched using the Web of Science, PMC/Medline via PubMed and Scopus databases up to May 2017 with no time and language limitation. After quality assessment, 9 articles were included in the study. All data extraction was conducted by two reviewers independently. Based on the results of the studies, it seems that mitochondrial DNA abnormality and mitochondrial dysfunction may be due to primary inflammation in MS or may be occurred itself before any inflammation, but definitely contributes to axonal degeneration and disease progression. Mitochondrial abnormality contributes to axonal degeneration in MS and disease progression

Modelling the functional genomics of Parkinson’s disease in Caenorhabditis elegans: LRRK2 and beyond

For decades, Parkinson’s disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes

Modelling the functional genomics of Parkinson’s in Caenorhabditis elegans: LRRK2 and beyond

For decades, Parkinson’s disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans, show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes

Experimental autoimmune encephalomyelitis from a tissue energy perspective

Increasing evidence suggests a key role for tissue energy failure in the pathophysiology of multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE), a commonly used model of MS, have been instrumental in illuminating the mechanisms that may be involved in compromising energy production. In this article, we review recent advances in EAE research focussing on factors that conspire to impair tissue energy metabolism, such as tissue hypoxia, mitochondrial dysfunction, production of reactive oxygen/nitrogen species, and sodium dysregulation, which are directly affected by energy insufficiency, and promote cellular damage. A greater understanding of how inflammation affects tissue energy balance may lead to novel and effective therapeutic strategies that ultimately will benefit not only people affected by MS but also people affected by the wide range of other neurological disorders in which neuroinflammation plays an important role

Autophagy - A Double-Edged Sword

The chapters in this book review the latest advances in the molecular mechanisms of autophagy, highlighting some of the most challenging research topics. The focus is mainly on how this basic cell defense mechanism comes into play in various pathologies, including liver diseases, myopathies, infectious diseases, cancers and neurodegenerative diseases. In these diseases, the contradictory autophagy roles of cell survival versus cell death emphasize the necessity of taking into account this double-edged nature in future development of already promising, autophagy- modulating, therapies

mTOR complex 2 - akt signaling is physically and functionally at mam

The target of rapamycin (TOR) is a conserved protein kinase and a central controller of growth. TOR can be part of two structurally and functionally distinct complexes, termed TOR complex 1 and TOR complex 2. Mammalian TOR complex 2 (mTORC2) is composed of mTOR, Rictor, Sin1 and mLST8. Both mTORC1 and mTORC2 are activated by growth factors. The mechanism via which growth factors regulate mTORC2 has been elusive until recently. mTORC2 binds ribosomes in a growth factor stimulated manner and this association is required for mTORC2 activity. mTOR complex 2 functions include control of spatial cell growth and metabolism and thus, mTORC2 deregulation has been linked to various disorders including cancer and diabetes. mTORC2 phosphorylates and thereby activates the AGC kinase family member Akt (PKB). Akt has many different targets and functions, not all of which depend on mTORC2 mediated Akt phosphorylation. In order to gain a better understanding of mTORC2 function, we asked where mTORC2 signaling is localized. A number of studies localized mTORC2, functionally or physically, either to the endoplasmic reticulum (ER) or to mitochondria.We investigated whether these seemingly unrelated observations concerning mTORC2 localization, might be the consequence of mTORC2 signaling at MAM. MAM or mitochondria-associated ER membrane is a quasi-synaptic subdomain between the ER and mitochondria. MAM plays a crucial role in the regulation of mitochondrial metabolism and cell survival by gating both the calcium flux and phospholipid trafficking between the ER and mitochondria. First, we analyzed mTORC2 subcellular localization. mTORC2 is localized to the ER adjacent to mitochondria and mTORC2 can be biochemically isolated from MAM structures. mTOR complex 2 interacts with the IP3R-Grp75-VDAC1 complex, a tether that connects ER and mitochondria at MAM. Insulin stimulates mTORC2 localization to MAM and mTORC2 interaction with the IP3R-Grp75-VDAC1 complex. MAM localization of mTORC2 depends on mTORC2-ribosome interaction. Next we investigated the function of mTORC2 at MAM. Rictor (mTORC2) knockout causes a decrease in MAM formation. Growth factors stimulate MAM formation via mTORC2 and the Akt substrate PACS2, a MAM resident protein. As expected for MAM deficient cells, mTORC2 disruption changes the calcium flux from the ER to mitochondria at MAM. Furthermore, we observe a reduction of Akt mediated phosphorylation of the MAM calcium channel IP3R upon Rictor knockout. Thus, mTORC2 signaling at MAM controls MAM mediated calcium release via the Akt targets PACS2 and IP3R. Since MAM disruption and calcium signaling both affect mitochondrial metabolism, we proceeded by analyzing the mitochondrial physiology of mTORC2 deficient cells. Rictor knockout cells exhibit a disruption of VDAC1-HK2 binding, caused by a lack of Akt mediated phosphorylation of HK2 at MAM. This, together with the defect in MAM, induces an increase in basal respiration, mitochondrial inner membrane potential, and ATP production in the mTORC2 deficient cells, culminating in apoptosis. Thus, mTORC2 at MAM appears to control several aspects of mitochondrial physiology. These findings emphasize the role of MAM as a signaling hub that controls cell physiology. By identifying the integral role of mTORC2 at the core of this platform, our results provide new insights on the mechanisms that regulate growth and metabolism. These observations may offer new therapeutic strategies against mTORC2 and MAM driven diseases such as diabetes, Alzheimer’s and cancer

Engagement of people with multiple sclerosis to enhance research into the physiological effect of hyperbaric oxygen therapy

BACKGROUND: Thousands of people with multiple sclerosis (MS) have used self-administered oxygen therapy in the UK. Clinical trials have been performed, with scant evidence that people with MS have been consulted to explore how they benefit from or how to optimize this treatment. The conventional MS disease disability scores used in trials seldom reflect the effects individuals report when using oxygen therapy to treat their symptoms. METHODS: Three people with MS and the manager of an MS Centre formed a public involvement group and collaborated with clinicians and scientists to inform a lab-based study to investigate the physiological effects of oxygen therapy on microvascular brain endothelial cells. RESULTS: People with MS often use oxygen therapy at a later stage when their symptoms worsen and only after using other treatments. The frequency of oxygen therapy sessions and hyperbaric pressure is individualized and varies for people with MS. Despite direct comparisons of efficacy proving difficult, most individuals are exposed to 100% O2 at 1.5 atmosphere absolute (ATA; 1140 mmHg absolute) for 60 min. In a laboratory-based study human brain endothelial cells were exposed in vitro to 152 mmHg O2 for 60 min with and without pressure, as this equates to 20% O2 achievable via hyperbarics, which was then replicated at atmospheric pressure. A significant reduction in endothelial cells ICAM-1 (CD54) implicated in inflammatory cell margination across the blood brain barrier was observed under oxygen treatment. CONCLUSIONS: By collaborating with people living with MS, we were able to design laboratory-based experimental protocols that replicate their treatment regimens to advance our understanding of the physiological effects of hyperbaric oxygen treatment on brain cells and their role in neuroinflammation

Calnexin Is Necessary for T Cell Transmigration into the Central Nervous System

In multiple sclerosis (MS), a demyelinating inflammatory disease of the CNS, and its animal model (experimental autoimmune encephalomyelitis; EAE), circulating immune cells gain access to the CNS across the blood-brain barrier to cause inflammation, myelin destruction, and neuronal damage. Here, we discovered that calnexin, an ER chaperone, is highly abundant in human brain endothelial cells of MS patients. Conversely, mice lacking calnexin exhibited resistance to EAE induction, no evidence of immune cell infiltration into the CNS, and no induction of inflammation markers within the CNS. Furthermore, calnexin deficiency in mice did not alter the development or function of the immune system. Instead, the loss of calnexin led to a defect in brain endothelial cell function that resulted in reduced T cell trafficking across the blood-brain barrier. These findings identify calnexin in brain endothelial cells as a potentially novel target for developing strategies aimed at managing or preventing the pathogenic cascade that drives neuroinflammation and destruction of the myelin sheath in MS