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The Journal of Neuroscience, January 3, 2018 • 38(1):29–31 • 29

Journal Club

Editor’s Note: These short reviews of recent JNeurosci articles, written exclusively by students or postdoctoral fellows, summarize the important findings of the paper and provide additional insight and commentary. If the authors of the highlighted article have written a response to the Journal Club, the response can be found by viewing the Journal Club at www.jneurosci.org. For more information on the format, review process, and purpose of Journal Club articles, please see http://jneurosci.org/content/ preparing-manuscript#journalclub.

A Therapeutic Link between and Remyelination in a Mouse Model of

Craig Pearson National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20824, and Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 1TN, United Kingdom Review of Feliu´ et al.

Injuries to the mammalian CNS often Among these molecules, substantial phase, the failure of remyelination in the provoke astrogliosis, a process in which attention has been paid to chondroitin progressive phase leads to extensive neu- reactive surround the site of in- sulfate proteoglycans (CSPGs), which are rodegeneration, resulting in severe dys- jury to restrict tissue damage (Voskuhl et proteins that inhibit function and disability (Franklin, 2002). al., 2009; Hamby and Sofroniew, 2010). neuronal growth in vivo and in vitro and Curiously, these demyelinated plaques are Formation of the glial has historically have been linked to remyelination failure not typically depleted of myelin-forming been viewed as a short-term solution that (Galtrey and Fawcett, 2007). Therapies (Chang et al., 2002). creates long-term problems: while astro- that selectively remove the inhibitory gly- The inability of oligodendrocytes in effectively limits the spread of in- cosaminoglycan (GAG) chains of CSPGs MS lesions to successfully remyelinate flammation and , it also creates a have been vital to studies of axon regener- damaged axons suggests that some aspect physical and chemical barrier to the re- ation and remyelination in many models of the lesion environment, such as astro- generation and remyelination of axons of CNS and disease (Soleman et al., gliosis, inhibits the remyelination process. (Cregg et al., 2014). Many therapies for 2013). Given the complexity of extracellular Astrocytes in the white matter of MS CNS have thus sought to remove responses to acute and chronic damage, it is lesions associate with CSPGs, and remy- this barrier by blocking astrogliosis and crucial to develop a clear understanding of elination tends to be more robust in areas restricting or neutralizing the . how therapeutic interventions modify the with fewer reactive astrocytes and lower However, in certain contexts, blocking re- inhibitory microenvironment to ensure levels of CSPGs, in conjunction with active formation has been found their success. higher numbers of pre- to impede functional recovery (Anderson One disease that might benefit from cursor cells (OPCs; Chang et al., 2012). et al., 2016), suggesting that some astro- treatments targeting CSPGs associated Furthermore, CSPGs inhibit OPC growth cytes may exert neuroprotective effects with astrogliosis is multiple sclerosis (MS), and differentiation in vitro, and enzymatic (Faulkner, 2004). Therefore, rather than an inflammatory disease characterized by digestion of their GAG chains reverses this prohibit astrogliosis entirely, alternative multiple focal regions of demyelination and inhibition (Siebert and Osterhout, 2011; therapies have sought to specifically tar- axonal damage, known as plaques, in the Lau et al., 2012; Pendleton et al., 2013). getmoleculesproducedbyreactiveastro- and (Compston and Coles, Moreover, in vivo therapies that block cytes that inhibit axon regeneration and 2008). At the time of diagnosis, most patients CSPG synthesis (Lau et al., 2012; Keough remyelination. exhibit a relapsing–relapsing remitting disease et al., 2016), digest GAG chains (Bartus et course, in which periods of disability are al., 2014), or disrupt CSPG receptors

Received Oct. 2, 2017; revised Nov. 6, 2017; accepted Nov. 7, 2017. followed by periods of recovery; however, (Lang et al., 2015) have all been shown I thank Dr. Alessia Tassoni and Irene Falk for comments on the manu- many patients eventually enter a second- to improve axon regeneration and remy- script. ary progressive phase in which disabilities elination, providing convincing evidence Correspondence should be addressed to Craig Pearson, National Insti- accumulate without recovery (Compston that CSPGs antagonize the remyelination tutes of Health, Building 50, Room 4142, Bethesda, MD 20817. E-mail: [email protected]. and Coles, 2008). Whereas demyelinated process. Together, these findings point DOI:10.1523/JNEUROSCI.2844-17.2017 axons in MS plaques may spontaneously to CSPGs as an important target for MS Copyright © 2018 the authors 0270-6474/18/380029-03$15.00/0 remyelinate in the relapsing–remitting therapies. 30 • J. Neurosci., January 3, 2018 • 38(1):29–31 Pearson • Journal Club

In an article published in The Journal of yet been explored. To produce elevated axon regeneration after Neuroscience, Feliu´ et al., (2017) describe a 2-AG levels in vivo, Feliu´ et al. (2017) in mice (Anderson et al., 2016), and it was pharmacological treatment that reduces pharmacologically inhibited the hydroly- recently discovered that reactive astro- CSPG deposition in demyelinating lesions sis of 2-AG by monoacylglycerol lipase cytes can be classified into at least two of the spinal cord and leads to improved (MAGL) using a reversible MAGL inhibi- subtypes, only one of which inhibits the motor function in a mouse model of MS, tor, UCM03025. After 10 d of treatment, repair of neuronal pathways (Liddelow et illustrating an important new link be- the MAGL inhibitor yielded significant al., 2017). This dichotomy extends to the tween CSPGs and remyelination (Feliu´ functional improvements in spontaneous molecules produced by reactive astrocy- et al., 2017). To study changes in the motor activity and reduced immuno- tes: emerging evidence shows that even extracellular environment of demyelinated staining for markers of reactive astrocytes CSPGs themselves, long considered an lesions, the researchers examined mice and CSPGs (Feliu´ et al., 2017). This indi- unequivocal barrier to axonal growth, can inoculated with Theiler’s murine enceph- cates that the previously demonstrated undertake both permissive and inhibitory alomyelitis virus (TMEV), which stimu- therapeutic effects of 2-AG administra- functions depending on their structural lates a progressive model of MS in which tion may be due in part to its reduction of features. For instance, it has been demon- the chronic phase is accompanied by as- astrocyte-derived CSPGs and that these strated that the different sulfation pat- trogliosis (Feliu´ et al., 2015). The spinal beneficial effects can be achieved by phar- terns of CSPG GAG chains influence how cords of TMEV-infected mice were ana- macologically inhibiting 2-AG hydrolysis. respond to these molecules, with lyzed at 85 d postinjury (dpi), during the In addition to reducing inhibitory com- chronic phase of the disease, and 105 dpi, ponents of the glial scar, inhibiting 2-AG cultured neurons avoiding 4-sulfated GAGs a well established time point for assess- hydrolysis increased the number of OPCs yet growing readily over 6-sulfated GAGs ing early remyelination (Warrington et and mature oligodendrocytes in the de- (Wang et al., 2008). Shifts in the ratio of al., 2000). Astrogliosis was evaluated by myelinated lesions of TMEV mice at 85 4-sulfated GAGs to 6-sulfated GAGs in immunostaining for GFAP and vimentin. dpi. Western blot analysis indicated that the brain were recently linked to age-related CSPG levels were measured using immu- levels of myelin basic protein were re- declines in plasticity in mice, suggesting that nostaining with an antibody (CS-56) spe- stored to sham levels in UCM03025- selective targeting of inhibitory GAG chain cific to the GAG chains of CSPGs, as well treated mice. This suggests that suppressing motifs may make for more effective thera- as with RT-PCR and Western blot. By 85 MAGL and elevating 2-AG enabled OPCs pies (Foscarin et al., 2017). dpi, a robust increase in reactive astro- to migrate to the lesion and differentiate More research is required to untangle cytes was observed in conjunction with into mature oligodendrocytes, thereby re- the complex interactions between neu- CSPG levels and increased expression of storing the endogenous mechanism of rons and their environment after injury or CSPG-related mRNA and proteins in remyelination. This observation was ex- disease. It would be valuable, for instance, demyelinated spinal cord lesions. CSPGs tended by assessing motor activity at 105 to study whether CSPG GAG chain sulfa- were closely associated with reactive as- dpi without further UCM03025 treat- tion changes after inhibiting 2-AG hydro- trocytes. Given the evidence that astrocy- ment. CSPG immunostaining and protein lysis in TMEV mice or whether selectively tes produce CSPGs following CNS injury levels remained lower in treated mice than targeting inhibitory sulfate groups with- (McKeon et al., 1999), this observation in controls, even at this later time point. out directly reducing CSPG levels might suggests that the CSPGs in TMEV mice Furthermore, lesions examined by trans- improve functional outcomes in a similar were likely produced by reactive astrocytes. mission electron microscopy at 105 dpi manner. The relationship between CSPGs, Encouragingly, treating mice with xylo- revealed newly formed myelin sheaths OPCs, and inflammatory cells also de- side, which inhibits CSPG synthesis, re- and an increase in myelinated axons in serves further investigation. Feliu´ et al., duced markers of astrogliosis and CSPGs, the spinal cords of mice treated with the (2017) found that inhibiting 2-AG hydro- and also rescued motor function as mea- MAGL inhibitor, supporting the conclu- lysis reduces microglial activation and sured by spontaneous motor activity (Fe- sion that remyelination was indeed taking IL-1␤ mRNA levels, suggesting that this liu´ et al., 2017). place. Interestingly, UCM03025 adminis- treatment also modulates the inflamma- Having confirmed that TMEV pro- tration led to reduced immunostaining tory response. Isolating the contributions duces demyelinated lesions characterized for a marker of microglial activation and of these various effects may prove chal- by reactive astrocytes and elevated CSPG lowered levels of mRNA for the immune lenging due to their interdependence. As deposition, Feliu´ et al. (2017) sought to mediator IL-1␤, indicating that 2-AG may the mechanisms underlying axon regen- determine whether the endogenous can- also play an immunomodulatory role. nabinoid 2-arachidonoylglycerol (2-AG) Understanding the mechanisms that eration and remyelination become better affects astrogliosis. 2-AG plays a central prevent remyelination in MS is vital to de- described, it is increasingly vital to eluci- role in promoting oligodendrocyte prolif- veloping effective therapies, particularly date how the extracellular matrix contrib- eration and differentiation (Gomez et al., for patients in the progressive phase of the utes to these injury response processes 2011; Gomez et al., 2015). Previous work disease. The discovery that enhancing en- and to develop therapeutic interventions showed that a single injection of 2-AG re- dogenous 2-AG levels also reduces CSPG that selectively and effectively promote duced white matter damage after spinal accumulation in demyelinated lesions is a neuronal repair. The findings reported cord injury in rats (Arevalo-Martin et al., significant step toward establishing a new by Feliu´ et al., (2017) expand our under- 2010) and that sustained delivery over therapeutic target. Our knowledge of the standing of how the glial scar contributes 14 d delayed disease onset in mice with role of the glial scar in tissue remodeling to the failure of remyelination in chronic experimental autoimmune encephalomy- after CNS injury has become increasingly disease and suggest promising future ave- elitis, another commonly used model of nuanced, with evidence that astrogliosis is nues of investigation and potential treat- MS (Lourbopoulos et al., 2011). However, not uniformly inhibitory to repair. Astro- ments for demyelinating conditions like the effects of 2-AG on astrogliosis had not cytic scar formation was found to support MS. Pearson • Journal Club J. Neurosci., January 3, 2018 • 38(1):29–31 •31

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