Chronic Progressive Multiple Sclerosis – Pathogenesis of Neurodegeneration and Therapeutic Strategies

Multiple sclerosis (MS) is an inflammatory, autoimmune, demyelinating disease of the central nervous system (CNS) that usually starts as a relapsing-remitting disease. In most patients the disease evolves into a chronic progressive phase characterized by continuous accumulation of neurological deficits. While treatment of relapsing-remitting MS (RRMS) has improved dramatically over the last decade, the therapeutic options for chronic progressive MS, both primary and secondary, are still limited. In order to find new pharmacological targets for the treatment of chronic progressive MS, the mechanisms of the underlying neurodegenerative process that becomes apparent as the disease progresses need to be elucidated. New animal models with prominent and widespread progressive degenerative components of MS have to be established to study both inflammatory and non-inflammatory mechanisms of neurodegeneration. Here, we discuss disease mechanisms and treatment strategies for chronic progressive MS

Actomyosin contractility controls cell surface area of oligodendrocytes

<p>Abstract</p> <p>Background</p> <p>To form myelin oligodendrocytes expand and wrap their plasma membrane multiple times around an axon. How is this expansion controlled?</p> <p>Results</p> <p>Here we show that cell surface area depends on actomyosin contractility and is regulated by physical properties of the supporting matrix. Moreover, we find that chondroitin sulfate proteoglycans (CSPG), molecules associated with non-permissive growth properties within the central nervous system (CNS), block cell surface spreading. Most importantly, the inhibitory effects of CSPG on plasma membrane extension were completely prevented by treatment with inhibitors of actomyosin contractility and by RNAi mediated knockdown of myosin II. In addition, we found that reductions of plasma membrane area were accompanied by changes in the rate of fluid-phase endocytosis.</p> <p>Conclusion</p> <p>In summary, our results establish a novel connection between endocytosis, cell surface extension and actomyosin contractility. These findings open up new possibilities of how to promote the morphological differentiation of oligodendrocytes in a non-permissive growth environment.</p> <p>See related minireview by Bauer and ffrench-Constant: <url>http://www.jbiol.com/content/8/8/78</url></p

Identification of Tmem10/Opalin as a novel marker for oligodendrocytes using gene expression profiling

<p>Abstract</p> <p>Background</p> <p>During the development of the central nervous system, oligodendrocytes generate large amounts of myelin, a multilayered insulating membrane that ensheathes axons, thereby allowing the fast conduction of the action potential and maintaining axonal integrity. Differentiation of oligodendrocytes to myelin-forming cells requires the downregulation of RhoA GTPase activity.</p> <p>Results</p> <p>To gain insights into the molecular mechanisms of oligodendrocyte differentiation, we performed microarray expression profiling of the oligodendroglial cell line, Oli-neu, treated with the Rho kinase (ROCK) inhibitor, Y-27632 or with conditioned neuronal medium. This resulted in the identification of the transmembrane protein 10 (Tmem10/Opalin), a novel type I transmembrane protein enriched in differentiating oligodendrocytes. In primary cultures, Tmem10 was abundantly expressed in O4-positive oligodendrocytes, but not in oligodendroglial precursor cells, astrocytes, microglia or neurons. In mature oligodendrocytes Tmem10 was enriched in the rims and processes of the cells and was only found to a lesser extent in the membrane sheets.</p> <p>Conclusion</p> <p>Together, our results demonstrate that Tmem10 is a novel marker for in vitro generated oligodendrocytes.</p

Targeted Ablation of Oligodendrocytes Triggers Axonal Damage

Glial dysfunction has been implicated in a number of neurodegenerative diseases. In this study we investigated the consequences of glial and oligodendrocyte ablation on neuronal integrity and survival in Drosophila and adult mice, respectively. Targeted genetic ablation of glia was achieved in the adult Drosophila nervous system using the GAL80-GAL4 system. In mice, oligodendrocytes were depleted by the injection of diphtheria toxin in MOGi-Cre/iDTR double transgenic animals. Acute depletion of oligodendrocytes induced axonal injury, but did not cause neuronal cell death in mice. Ablation of glia in adult flies triggered neuronal apoptosis and resulted in a marked reduction in motor performance and lifespan. Our study shows that the targeted depletion of glia triggers secondary neurotoxicity and underscores the central contribution of glia to neuronal homeostasis. The models used in this study provide valuable systems for the investigation of therapeutic strategies to prevent axonal or neuronal damage

Neuron to glia signaling triggers myelin membrane exocytosis from endosomal storage sites

During vertebrate brain development, axons are enwrapped by myelin, an insulating membrane produced by oligodendrocytes. Neuron-derived signaling molecules are temporally and spatially required to coordinate oligodendrocyte differentiation. In this study, we show that neurons regulate myelin membrane trafficking in oligodendrocytes. In the absence of neurons, the major myelin membrane protein, the proteolipid protein (PLP), is internalized and stored in late endosomes/lysosomes (LEs/Ls) by a cholesterol-dependent and clathrin-independent endocytosis pathway that requires actin and the RhoA guanosine triphosphatase. Upon maturation, the rate of endocytosis is reduced, and a cAMP-dependent neuronal signal triggers the transport of PLP from LEs/Ls to the plasma membrane. These findings reveal a fundamental and novel role of LEs/Ls in oligodendrocytes: to store and release PLP in a regulated fashion. The release of myelin membrane from LEs/Ls by neuronal signals may represent a mechanism to control myelin membrane growth

Disease modification in multiple sclerosis by flupirtine-results of a randomized placebo controlled phase II trial

Central nervous system inflammation and neurodegeneration are the pathophysiological hallmarks of multiple sclerosis (MS). While inflammation can readily be targeted by current disease modifying drugs, neurodegeneration is by far less accessible to treatment. Based on suggested additional neuroprotective capacities of the orally available non-opioid and centrally acting analgesic drug flupirtine maleate we hypothesized that treatment with flupirtine maleate might be beneficial in MS patients. The flupirtine as oral treatment in multiple sclerosis (FLORIMS) study was a multi-center, randomized and stratified, placebo-controlled double-blind phase II trial to investigate safety and efficacy in terms of clinical and radiographical activity of flupirtine maleate (300 mg per day) given orally for 12 months, add-on to interferon beta 1b subcutaneously in patients with relapsing remitting MS. Due to a substantial delay in recruitment, enrolment of patients was prematurely terminated after randomization of only 30 of the originally planned 80 patients. Of these, 24 regularly terminated study after 12 months of treatment. Data were analyzed as originally planned. Treatment with flupirtine maleate was overall well tolerated. We observed moderate and asymptomatic elevations of liver enzymes in several cases but no overt hepatotoxicity. Neither the intention to treat nor the per protocol analysis revealed any significant treatment effects of flupirtine maleate with respect to occurrence of MS relapses, disability progression, or development of new lesions on cranial MRI. However, substantial methodological limitations need to be considered when interpreting these results. In conclusion, the results of the FLORIMS study neither add further evidence to nor argue against the hypothesized neuroprotective or disease modifying effects of flupirtine maleate in MS

A developmental analysis of juxtavascular microglia dynamics and interactions with the vasculature [preprint]

Microglia, the resident macrophages of the central nervous system (CNS), are dynamic cells, constantly extending and retracting their processes as they contact and functionally regulate neurons and other glial cells. There is far less known about microglia-vascular interactions, particularly under healthy steady-state conditions. Here, we use the male and female mouse cerebral cortex to show that a higher percentage of microglia associate with the vasculature during the first week of postnatal development compared to older ages and the timing of these associations are dependent on the fractalkine receptor (CX3CR1). Similar developmental microglia-vascular associations were detected in the prenatal human brain. Using live imaging in mice, we found that juxtavascular microglia migrated when microglia are actively colonizing the cortex and became stationary by adulthood to occupy the same vascular space for nearly 2 months. Further, juxtavascular microglia at all ages contact vascular areas void of astrocyte endfeet and the developmental shift in microglial migratory behavior along vessels corresponded to when astrocyte endfeet more fully ensheath vessels. Together, our data provide a comprehensive assessment of microglia-vascular interactions. They support a mechanism by which microglia use the vasculature to migrate within the developing brain parenchyma. This migration becomes restricted upon the arrival of astrocyte endfeet when juxtavascular microglia then establish a long-term, stable contact with the vasculature

A Developmental Analysis of Juxtavascular Microglia Dynamics and Interactions with the Vasculature

Microglia, a resident CNS macrophage, are dynamic cells, constantly extending and retracting their processes as they contact and functionally regulate neurons and other glial cells. There is far less known about microglia-vascular interactions, particularly under healthy steady-state conditions. Here, we use the male and female mouse cerebral cortex to show that a higher percentage of microglia associate with the vasculature during the first week of postnatal development compared with older ages and that the timing of these associations is dependent on the fractalkine receptor (CX3CR1). Similar developmental microglia-vascular associations were detected in the human brain. Using live imaging in mice, we found that juxtavascular microglia migrated when microglia are actively colonizing the cortex and became stationary by adulthood to occupy the same vascular space for nearly 2 months. Further, juxtavascular microglia at all ages associate with vascular areas void of astrocyte endfeet, and the developmental shift in microglial migratory behavior along vessels corresponded to when astrocyte endfeet more fully ensheath vessels. Together, our data provide a comprehensive assessment of microglia-vascular interactions. They support a mechanism by which microglia use the vasculature to migrate within the developing brain parenchyma. This migration becomes restricted on the arrival of astrocyte endfeet such that juxtavascular microglia become highly stationary and stable in the mature cortex. SIGNIFICANCE STATEMENT We report the first extensive analysis of juxtavascular microglia in the healthy, developing, and adult brain. Live imaging revealed that juxtavascular microglia within the cortex are highly motile and migrate along vessels as they are colonizing cortical regions. Using confocal, expansion, super-resolution, and electron microscopy, we determined that microglia associate with the vasculature at all ages in areas lacking full astrocyte endfoot coverage and motility of juxtavascular microglia ceases as astrocyte endfeet more fully ensheath the vasculature. Our data lay the fundamental groundwork to investigate microglia-astrocyte cross talk and juxtavascular microglial function in the healthy and diseased brain. They further provide a potential mechanism by which vascular interactions facilitate microglial colonization of the brain to later regulate neural circuit development