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Inflammatory-Mediated Neuron-Glia Communication Modulates ALS Pathophysiology

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Inflammatory-Mediated Neuron-Glia Communication Modulates ALS Pathophysiology 1142 • The Journal of Neuroscience, February 10, 2021 • 41(6):1142–1144 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/jneurosci-journal-club. Inflammatory-Mediated Neuron-Glia Communication Modulates ALS Pathophysiology Juliani Juliani, Natasha Vassileff, and Jereme G. Spiers Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria 3083, Australia Review of Dutta et al. Amyotrophic lateral sclerosis (ALS) is the by neuronal interactions with infiltrat- and subsequent proteasomal degradation, most common adult-onset motor neuron ing peripheral immune cells, such as selectively in neurons in TDP-43 and disease. It is characterized by the deposi- lymphocytes, and with activated glial SOD-1 mouse models of ALS. Importantly, tion of aggregated proteins and predomi- cells, including microglia (Komine and expression of mutant IkBa (IkBa-SR) nantly affects motor neurons and the Yamanaka, 2015). During the early de- reduced molecular and behavioral hall- motor cortex. Although ALS is a geneti- velopment of ALS, microglia adopt a marks of ALS pathogenesis. Expression of cally heterogeneous disease, mutations so-called M2 activation state, in which IkBa-SR in TDP-43 mutant mice reduced in superoxide dismutase 1 (SOD-1) and they release neuroprotective factors, the nuclear translocation of the p65 subunit transactive response DNA-binding pro- such as anti-inflammatory cytokines of NFkB, thus reducing neuroinflammatory tein 43 (TDP-43), encoded by TARDBP, and neurotrophic factors (Suh et al., NFkB signaling. This was associated with are the most prevalent. SOD-1 mutations 2013; Gravel et al., 2016; Zhang et al., reduced cytoplasmic accumulation of TDP- are frequent in familial ALS, whereas 2018). But as the disease progresses, 43 in spinal motor neurons compared with TDP-43 is linked to sporadic ALS, with microglia polarize toward an M1 acti- TDP-43 mutant controls expressing WT 97% of all sporadic cases exhibiting vation state, in which they release pro- IkBa. Moreover, spinal cord extracts from TDP-43 protein aggregates (Scotter et al., inflammatory cytokines and reactive single TDP-43 mutant mice exhibited 2015). oxygen species, both of which are toxic higher levels of insoluble TDP-43 than dou- Transgenic mice expressing mutant in motor neurons (Liao et al., 2012; Liu ble-transgenic IkBa-SR;TDP-43 mice. This SOD-1 or mutant TDP-43 are the favored and Wang, 2017). The M1 activation suggests that neuron-specific reduction in k animal models for studying ALS in vivo,and state is induced by NFkB, a transcrip- NF B signaling reduced TDP-43 protein these well-established models recapitulate tion factor that serves as a master regula- aggregation in mice. many features observed in ALS patients, tor of inflammation. NFkB is upregulated Because gliosis is one of the key including TDP-43-related neurodegenera- in ALS and is a major trigger of microglial- changes associated with neuroinflamma- tionandarapiddiseaseprogression(Joyce induced motor neuron death (Swarup et tion in the pathophysiology of ALS, Dutta k a et al., 2011). Mutant SOD-1 and mutant al., 2011; Frakes et al., 2014). Because et al. (2020) asked how I B -SR expression TDP-43 mice also develop protein aggre- TDP-43 is a known activator of NFkB, in TDP-43 mice affected markers of glial gates resulting in neuroinflammation and dysregulation of TDP-43 is suggested to be activation, specifically astrocytic GFAP and motor neuron death, greatly enhancing their a key factor driving NFkBupregulation microglial ionized calcium binding adaptor relevance in ALS research (Wegorzewska et and neuroinflammation in ALS pathoge- molecule 1 (Iba1). Significant reductions in al., 2009; Gill et al., 2019). nesis (Swarup et al., 2011). both markers were observed relative to con- Neuroinflammation is a vital compo- To further investigate the links between trol TDP-43 mice, suggesting that the neu- nent of ALS pathogenesis. It is mediated NFkB, neuroinflammation, and ALS patho- ronal reduction in NFkBsignalingwas genesis, a recent article by Dutta et al. (2020) sufficient to modulate gliosis. In addition, published in The Journal of Neuroscience the authors used immunofluorescent stain- Received July 28, 2020; revised Nov. 1, 2020; accepted Dec. 17, 2020. examined the effects of expressing a neuron- ing to examine astrocytes and microglia, The authors declare no competing financial interests. specific super-repressor of NFkBsignaling focusing on microglial morphology. Resting *Correspondence should be addressed to Natasha Vassileff at in mice. Specifically, the authors expressed a microglial cells have a densely branched [email protected]. k k a “ ” https://doi.org/10.1523/JNEUROSCI.1970-20.2020 form of the NF B inhibitor I B ,which ramified morphology, whereas acti- Copyright © 2021 the authors was modified to prevent phosphorylation vated microglia exhibit less branching Juliani et al. · Neuron-Glia Communication Modulates ALS J. Neurosci., February 10, 2021 • 41(6):1142–1144 • 1143 and become amoeboid to facilitate mo- a process critical for the maintenance of gliosis, including excessive M1 microglial bility and phagocytosis. Whereas micro- synaptic function, information process- polarization, and this was alleviated with glia in control TDP-43 mutant mice had ing, and neuronal health (Sheridan and neuron-specific suppression of NFkBsig- relatively few, and short branches in Murphy, 2013). Although the exact role naling.Thissuggeststhatcrosstalkbetween addition to intense Iba1 staining, double- of fractalkine within the CNS is not com- neuronsandmicrogliaiscriticalinALS transgenic IkBa-SR;TDP-43 mice had pletely understood, multiple studies have pathophysiology. Moreover, reductions in more ramified branch patterns and Iba1 suggested that fractalkine signaling has neuronal NFkB signaling increased autoph- levels similar to WT controls. an anti-inflammatory effect by modulating agy activity, suggesting that neuroinflam- Dutta et al. (2020) also observed an microglial polarization toward the neuro- matory tone contributes to neuronal increase in autophagy in the spinal cord of protective M2 phenotype (Liao et al., 2012; protein detoxification efficiency, which is mice expressing both IkBa-SR and mu- Zhang et al., 2018). Importantly, abnormal critical for maintaining neuronal health. tant TDP-43 compared with mice express- neuron-glia communication has previously Previous work has shown that neuron-glia ingmutantTDP-43alone.Thisisnotable been observed in a mouse model of ALS, communication via chemokine mediators, because dysregulation of autophagy is with these mice expressing lower fractal- such as fractalkine, plays an important role thought to contribute to ALS progression. kine levels accompanied by increased in restoring homeostatic microglial function MutatedTDP-43andSOD-1havebeen polarization of microglia toward a neu- and maintaining autophagy. However, the implicated in propagating ALS pathogene- rotoxic M1 phenotype (Zhang et al., interaction between inflammatory signaling, sis through the induction of aberrant 2018). Treatment with pro-inflammatory neuron-glia communication, and ALS autophagy, a cellular process involved in lipopolysaccharide, a well-established NFkB pathogenesis is complex and requires packaging organelles and protein aggre- activator, significantly reduces brain expres- much further characterization of the gates destined for lysosomal degradation. sion of fractalkine, leading to increased neuroinflammatory mechanisms involved TDP-43 and SOD-1 transcriptionally regu- inflammatory microglial activation (Harland in the early potentiation of ALS motor neu- late and influence several proteins involved et al., 2020). Moreover, these effects were ron death. in autophagy (Bose et al., 2011; Lee et al., specific for the neuronal fractalkine ligand, 2015; Ying et al., 2016; Massenzio et al., with viral knockdown of neuronal fractal- References 2018). Furthermore, mutated forms of kine increasing inflammatory microglial Bose JK, Huang CC, Shen CK (2011) Regulation of TDP-43 upregulate autophagy markers in activation (Harland et al., 2020). This sug- autophagy by neuropathological protein TDP- ALS patient tissues, whereas mutated gests that excessive inflammation evident in 43. J Biol Chem 286:44441–44448. SOD-1 proteins have been linked to an ALS may precipitate aberrant fractalkine- Ding X, Ma M, Teng J, Teng RK, Zhou S, Yin J, increase in autophagic vacuoles in mouse mediated neuron-glia signaling, stimulating Fonkem E, Huang JH, Wu E, Wang X (2015) motor neurons (Ding et al., 2015; Wang et harmful microglial polarization, causing ex- Exposure to ALS-FTD-CSF generates TDP-43 al., 2015; Xie et al., 2015). In addition, dele- cessive neuroinflammation and motor neu- aggregates in glioblastoma cells through exo- somes and TNTs-like structure. Oncotarget tion of Beclin-1, an important autophagy ron death. 6:24178–24191. regulator in mutant SOD-1 mice, was Furthermore, fractalkine signaling has Dutta K, Thammisetty SS, Boutej H, Bareil
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