scholarly journals The central role of mitochondria in axonal degeneration in multiple sclerosis

2014 ◽  
Vol 20 (14) ◽  
pp. 1806-1813 ◽  
Author(s):  
Graham R Campbell ◽  
Joseph T Worrall ◽  
Don J Mahad
Keyword(s):  
Multiple Sclerosis ◽  
Axonal Degeneration ◽  
Neuronal Cell ◽  
Mitochondrial Respiratory Chain ◽  
Respiratory Chain Complexes ◽  
Autoimmune Encephalomyelitis ◽  
Mitochondrial Abnormalities ◽  
Neuronal Cell Bodies ◽  
Chain Complexes

Neurodegeneration in multiple sclerosis (MS) is related to inflammation and demyelination. In acute MS lesions and experimental autoimmune encephalomyelitis focal immune attacks damage axons by injuring axonal mitochondria. In progressive MS, however, axonal damage occurs in chronically demyelinated regions, myelinated regions and also at the active edge of slowly expanding chronic lesions. How axonal energy failure occurs in progressive MS is incompletely understood. Recent studies show that oligodendrocytes supply lactate to myelinated axons as a metabolic substrate for mitochondria to generate ATP, a process which will be altered upon demyelination. In addition, a number of studies have identified mitochondrial abnormalities within neuronal cell bodies in progressive MS, leading to a deficiency of mitochondrial respiratory chain complexes or enzymes. Here, we summarise the mitochondrial abnormalities evident within neurons and discuss how these grey matter mitochondrial abnormalities may increase the vulnerability of axons to degeneration in progressive MS. Although neuronal mitochondrial abnormalities will culminate in axonal degeneration, understanding the different contributions of mitochondria to the degeneration of myelinated and demyelinated axons is an important step towards identifying potential therapeutic targets for progressive MS.

scholarly journals Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Barakat Alrashdi ◽  
Bassel Dawod ◽  
Andrea Schampel ◽  
Sabine Tacke ◽  
Stefanie Kuerten ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Retinal Ganglion Cells ◽  
Axonal Degeneration ◽  
Ganglion Cells ◽  
Neuronal Degeneration ◽  
Retinal Ganglion ◽  
Autoimmune Encephalomyelitis ◽  
Aav Vector ◽  
Α Subunit

Abstract Background In multiple sclerosis (MS) and in the experimental autoimmune encephalomyelitis (EAE) model of MS, the Nav1.6 voltage-gated sodium (Nav) channel isoform has been implicated as a primary contributor to axonal degeneration. Following demyelination Nav1.6, which is normally co-localized with the Na+/Ca2+ exchanger (NCX) at the nodes of Ranvier, associates with β-APP, a marker of neural injury. The persistent influx of sodium through Nav1.6 is believed to reverse the function of NCX, resulting in an increased influx of damaging Ca2+ ions. However, direct evidence for the role of Nav1.6 in axonal degeneration is lacking. Methods In mice floxed for Scn8a, the gene that encodes the α subunit of Nav1.6, subjected to EAE we examined the effect of eliminating Nav1.6 from retinal ganglion cells (RGC) in one eye using an AAV vector harboring Cre and GFP, while using the contralateral either injected with AAV vector harboring GFP alone or non-targeted eye as control. Results In retinas, the expression of Rbpms, a marker for retinal ganglion cells, was found to be inversely correlated to the expression of Scn8a. Furthermore, the gene expression of the pro-inflammatory cytokines Il6 (IL-6) and Ifng (IFN-γ), and of the reactive gliosis marker Gfap (GFAP) were found to be reduced in targeted retinas. Optic nerves from targeted eyes were shown to have reduced macrophage infiltration and improved axonal health. Conclusion Taken together, our results are consistent with Nav1.6 promoting inflammation and contributing to axonal degeneration following demyelination.

Insights in pathogenesis of multiple sclerosis: nitric oxide may induce mitochondrial dysfunction of oligodendrocytes

2017 ◽  
Vol 29 (1) ◽  
pp. 39-53 ◽  
Author(s):  
Minghong Lan ◽  
Xiaoyi Tang ◽  
Jie Zhang ◽  
Zhongxiang Yao
Keyword(s):  
Nitric Oxide ◽  
Multiple Sclerosis ◽  
Axonal Degeneration ◽  
Mitochondrial Respiratory Chain ◽  
Pathological Process ◽  
Demyelinating Diseases ◽  
Monocarboxylate Transporter ◽  
Respiratory Chain Complexes ◽  
Monocarboxylate Transporter 1 ◽  
Demyelinating Lesions

Abstract Demyelinating diseases, such as multiple sclerosis (MS), are kinds of common diseases in the central nervous system (CNS), and originated from myelin loss and axonal damage. Oligodendrocyte dysfunction is the direct reason of demyelinating lesions in the CNS. Nitric oxide (NO) plays an important role in the pathological process of demyelinating diseases. Although the neurotoxicity of NO is more likely mediated by peroxynitrite rather than NO itself, NO can impair oligodendrocyte energy metabolism through mediating the damaging of mitochondrial DNA, mitochondrial membrane and mitochondrial respiratory chain complexes. In the progression of MS, NO can mainly mediate demyelination, axonal degeneration and cell death. Hence, in this review, we extensively discuss endangerments of NO in oligodendrocytes (OLs), which is suggested to be the main mediator in demyelinating diseases, e.g. MS. We hypothesize that NO takes part in MS through impairing the function of monocarboxylate transporter 1, especially causing axonal degeneration. Then, it further provides a new insight that NO for OLs may be a reliable therapeutic target to ameliorate the course of demyelinating diseases.

scholarly journals Assembly factors monitor sequential hemylation of cytochrome b to regulate mitochondrial translation

2014 ◽  
Vol 205 (4) ◽  
pp. 511-524 ◽  
Author(s):  
Markus Hildenbeutel ◽  
Eric L. Hegg ◽  
Katharina Stephan ◽  
Steffi Gruschke ◽  
Brigitte Meunier ◽  
...  
Keyword(s):  
Electron Transport ◽  
Cytochrome B ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Mitochondrial Translation ◽  
Respiratory Chain Complexes ◽  
Mitochondrial Inner Membrane ◽  
Sequence Of Events ◽  
Chain Complexes ◽  
Assembly Factors

Mitochondrial respiratory chain complexes convert chemical energy into a membrane potential by connecting electron transport with charge separation. Electron transport relies on redox cofactors that occupy strategic positions in the complexes. How these redox cofactors are assembled into the complexes is not known. Cytochrome b, a central catalytic subunit of complex III, contains two heme bs. Here, we unravel the sequence of events in the mitochondrial inner membrane by which cytochrome b is hemylated. Heme incorporation occurs in a strict sequential process that involves interactions of the newly synthesized cytochrome b with assembly factors and structural complex III subunits. These interactions are functionally connected to cofactor acquisition that triggers the progression of cytochrome b through successive assembly intermediates. Failure to hemylate cytochrome b sequesters the Cbp3–Cbp6 complex in early assembly intermediates, thereby causing a reduction in cytochrome b synthesis via a feedback loop that senses hemylation of cytochrome b.

Neurons controlling cardiovascular responses to emotion are located in lateral hypothalamus-perifornical region

1990 ◽  
Vol 259 (5) ◽  
pp. R943-R954 ◽  
Author(s):  
O. A. Smith ◽  
J. L. DeVito ◽  
C. A. Astley
Keyword(s):  
Electrical Stimulation ◽  
Lateral Hypothalamus ◽  
Axonal Degeneration ◽  
Neuronal Cell ◽  
Cardiovascular Responses ◽  
Ibotenic Acid ◽  
Defense Reaction ◽  
Autonomic Responses ◽  
Neuronal Cell Bodies ◽  
Thoracic Cord

We did four experiments to determine whether the lateral hypothalamus-perifornical (LH/PF) region is the source of neuronal cell bodies responsible for producing the cardiovascular (CV) responses associated with emotion or the defense reaction. Of particular concern was whether the paraventricular nucleus (PVN) plays a role in the generation of these CV responses. Mapping the hypothalamus with electrical stimulation showed that the CV pattern of responses was never produced by stimulating the PVN and was invariably produced by stimulating the LH/PF region. Complete electrolytic destruction of the PVN and subsequent axonal degeneration did not change the CV pattern of responses elicited by LH/PF stimulation, whereas any encroachment of the lesion on the LH/PF region decreased the magnitude of the CV responses. Injection of the neuroexcitotoxin ibotenic acid (Ibo) into the PVN did not affect responses to LH/PF stimulation, whereas Ibo injection into the LH/PF region eliminated or severely attenuated the CV responses. Retrograde labeling of cells from the thoracic cord and the ventrolateral reticular formation revealed a scattered group of cells in the LH/PF region that may be the cells controlling the CV responses. These results point directly to the LH/PF region as the source of the cell bodies responsible for the autonomic responses associated with emotion or defense reactions.

scholarly journals The Immune-Modulatory Role of Apolipoprotein E with Emphasis on Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Hong-Liang Zhang ◽  
Jiang Wu ◽  
Jie Zhu
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Apolipoprotein E ◽  
T Cell Proliferation ◽  
Special Focus ◽  
Autoimmune Encephalomyelitis ◽  
Multiple Functions ◽  
Lipid Antigen ◽  
Experimental Autoimmune

Apolipoprotein E (apoE) is a 34.2 kDa glycoprotein characterized by its wide tissue distribution and multiple functions. The nonlipid-related properties of apoE include modulating inflammation and oxidation, suppressing T cell proliferation, regulating macrophage functions, and facilitating lipid antigen presentation by CD1 molecules to natural killer T (NKT) cells, and so forth. Increasing studies have revealed that APOEεallele might be associated with multiple sclerosis (MS), although evidence is still not sufficient enough. In this review, we summarized the current progress of the immunomodulatory functions of apoE, with special focus on the association of APOEεallele with the clinical features of MS and of its animal model experimental autoimmune encephalomyelitis (EAE).

Role of vasopressin in sympathetic response to paraventricular nucleus stimulation in anesthetized rats

1994 ◽  
Vol 266 (1) ◽  
pp. R228-R236 ◽  
Author(s):  
S. C. Malpas ◽  
J. H. Coote
Keyword(s):  
Paraventricular Nucleus ◽  
Neuronal Cell ◽  
Detection Algorithm ◽  
Homocysteic Acid ◽  
Renal Sympathetic Nerve Activity ◽  
Anesthetized Rats ◽  
Neuronal Cell Bodies ◽  
Peak Detection Algorithm ◽  
Glass Micropipette

Vasopressin may play an extrahypothalamic role in the central control of the cardiovascular system, specifically acting as a spinal neurotransmitter in the pathway where the paraventricular nucleus (PVN) alters sympathetic outflow. In this study, the effect of stimulating neuronal cell bodies in the PVN on renal sympathetic nerve activity (RSNA) and the possible involvement of vasopressin in the pathway was investigated in anesthetized rats. The PVN was stimulated by microinjection with 0.2 M D,L-homocysteic acid via a glass micropipette, and the hemodynamic and sympathetic responses were recorded. A computerized sympathetic peak-detection algorithm was applied to recordings of sympathetic discharges to retrieve information about the characteristics of RSNA during PVN stimulation. The algorithm scanned the series of RSNA voltages for significant increases followed by significant decreases in a small cluster of voltage values. Once each synchronized RSNA peak had been detected, its corresponding amplitude and peak-to-peak interval were calculated. PVN stimulation consistently increased the amplitude of RSNA (mean 30 +/- 5.6% over control), arterial pressure, and the peak-to-peak interval of discharges. A V1 vasopressin antagonist intrathecally administered as a 500-pmol dose was subsequently able to completely block the hemodynamic response (blood pressure increase of 14 +/- 5%) and a 35 +/- 6% increase in RSNA in response to PVN stimulation and intrathecal vasopressin. Thus spinal vasopressin is likely to be a neurotransmitter involved in the cardiovascular regulation involving the PVN.

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