sign in sign up
<<
Home , Motor neuron

1142 • The Journal of , 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 - 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 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 (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- . 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 (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, 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 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 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 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 C, reported to impair autophagy, increase been shown to regulate autophagy, which Julien JP (2020) Mitigation of ALS pathology motor neuron loss, escalate SOD-1 aggre- is crucial for clearing protein aggregates in by neuron-specific inhibition of nuclear factor gation, and upregulate microglial activa- the cytoplasm of spinal neurons (Hebron kappa B signaling. J Neurosci 40:5137–5154. tion relative to that seen in control mice. et al., 2014). Interestingly, in transgenic Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Thus, impaired autophagy appears to exac- ALS mouse models, loss of fractalkine sig- Schmelzer L, Braun L, Miranda CJ, Ladner KJ, Bevan AK, Foust KD, Godbout JP, Popovich erbate ALS pathogenesis (Tokuda et al., naling disrupted the autophagy-lysosome PG, Guttridge DC, Kaspar BK (2014) 2016). Together, the results presented by degradation pathway, and this was accom- Microglia induce motor neuron death via the Dutta et al. (2020) indicate that inhibition panied by abnormal protein accumulation classical NF-kB pathway in amyotrophic lat- of neuronal NFkB signaling can signifi- (Liu et al., 2019). Additionally, loss of frac- eral sclerosis. Neuron 81:1009–1023. cantly attenuate neuroinflammatory glial talkine signaling resulted in faster disease Gill C, Phelan JP, Hatzipetros T, Kidd JD, activation, stimulate autophagy, and progression and significantly shorter life- TassinariVR,LevineB,WangMZ,MorenoA, Thompson K, Maier M, Grimm J, Gill A, reduce TDP-43 protein aggregates typ- span in transgenic ALS mice, further indi- Vieira FG (2019) SOD1-positive aggregate ically observed during the pathogene- cating the importance of this signaling accumulation in the CNS predicts slower dis- sis of ALS. pathway in the pathophysiology of ALS ease progression and increased longevity in a One factor that might explain both (Liu et al., 2019). mutant SOD1 mouse model of ALS. Sci Rep the reduction in microglial activation Understanding how dysregulated 9:6724. and the increase in autophagy is disrup- NFkB signaling is involved in ALS and Gravel M, Béland LC, Soucy G, Abdelhamid E, tion in fractalkine signaling, a critical other neurodegenerative diseases is crit- Rahimian R, Gravel C, Kriz J (2016) IL-10 con- trols early microglial phenotypes and disease intercellular communication pathway ical for identifying potential therapeutic k onset in ALS caused by misfolded superoxide modulated by NF Bthatbecomesdys- strategies. With a focus on the TDP-43 dismutase 1. J Neurosci 36:1031–1048. regulated in numerous brain disorders, mouse model, using specific suppres- Harland M, Torres S, Liu J, Wang X (2020) including ALS (Harland et al., 2020; sion of neuronal NFkB, Dutta et al. Neuronal mitochondria modulation of LPS- Pawelec et al., 2020). Fractalkine is a che- (2020) have provided strong evidence induced neuroinflammation. J Neurosci mokine that is constitutively expressed that activation of this signaling pathway 40:1756–1765. by neurons, whereas its is solely in neurons contributes to harmful neu- Hebron ML, Algarzae NK, Lonskaya I, Moussa C (2014) Fractalkine signaling and Tau hyper- expressed by microglia (Harland et al., roinflammatory processes resulting in phosphorylation are associated with autopha- 2020). Fractalkine signaling has been toxic proteinopathy and motor neuron gic alterations in lentiviral Tau and Ab 1-42 identified as an integral means of media- death. Increased motor neuron death gene transfer models. Exp Neurol 251:127– ting neuron-microglia crosstalk, which is was observed along with increased 138. 1144 • J. Neurosci., February 10, 2021 • 41(6):1142–1144 Juliani et al. · Neuron-Glia Communication Modulates ALS

Joyce PI, Fratta P, Fisher EM, Acevedo-Arozena A Piffaretti D, Monti B (2018) Microglial overex- superoxide dismutase. Acta Neuropathol (2011) SOD1 and TDP-43 animal models of pression of fALS-linked mutant SOD1 indu- Commun 4:6. amyotrophic lateral sclerosis: recent advances ces SOD1 processing impairment, activation Wang X, Zhou S, Ding X, Ma M, Zhang J, Zhou Y, in understanding disease toward the develop- and neurotoxicity and is counteracted by Wu E, Teng J (2015) Activation of ER stress ment of clinical treatments. Mamm Genome the autophagy inducer trehalose. Biochim and autophagy induced by TDP-43 A315T as 22:420–448. Biophys Acta Mol Basis Dis 1864:3771– pathogenic mechanism and the corresponding Komine O, Yamanaka K (2015) Neuroinflammation 3785. histological changes in skin as potential bio- in . Nagoya J Med Sci Pawelec P, Ziemka-Nalecz M, Sypecka J, Zalewska marker for ALS with the mutation. Int J Biol – 77:537 549. T (2020) The impact of the CX3CL1/CX3CR1 Sci 11:1140–1149. Lee JY, Kawaguchi Y, Li M, Kapur M, Choi SJ, axis in neurological disorders. Cells 9:2277. Wegorzewska I, Bell S, Cairns NJ, Miller TM, Kim HJ, Park SY, Zhu H, Yao TP (2015) Scotter EL, Chen HJ, Shaw CE (2015) TDP-43 Baloh RH (2009) TDP-43 mutant transgenic Uncoupling of protein aggregation and neuro- proteinopathy and ALS: insights into dis- mice develop features of ALS and frontotem- degeneration in a mouse amyotrophic lateral ease mechanisms and therapeutic targets. poral lobar degeneration. Proc Natl Acad Sci sclerosis model. Neurodegener Dis 15:339– Neurotherapeutics 12:352–363. USA 106:18809–18814. 349. Sheridan GK, Murphy KJ (2013) Neuron-glia XieY,ZhouB,LinMY,WangS,FoustKD,Sheng Liao B, Zhao W, Beers DR, Henkel JS, Appel SH crosstalk in health and disease: fractalkine ZH (2015) Endolysosomal deficits augment (2012) Transformation from a neuroprotective and CX3CR1 take centre stage. Open Biol mitochondria pathology in spinal motor neu- to a neurotoxic microglial phenotype in a 3:130181. – rons of asymptomatic fALS mice. Neuron mouse model of ALS. Exp Neurol 237:147 Suh HS, Zhao ML, Derico L, Choi N, Lee SC – 152. (2013) Insulin-like growth factor 1 and 2 87:355 370. LiuC,HongK,ChenH,NiuY,DuanW,LiuY,Ji (IGF1, IGF2) expression in human microglia: Ying Z, Xia Q, Hao Z, Xu D, Wang M, Wang H, Y, Deng B, Li Y, Li Z, Wen D, Li C (2019) differential regulation by inflammatory media- Wang G (2016) TARDBP/TDP-43 regulates Evidence for a protective role of the CX3CL1/ tors. J Neuroinflammation 10:37. autophagy in both MTORC1-dependent and CX3CR1 axis in a model of amyotrophic lateral Swarup V, Phaneuf D, Dupré N, Petri S, Strong M, MTORC1-independent manners. Autophagy sclerosis. Biol Chem 400:651–661. Kriz J, Julien JP (2011) Deregulation of TDP- 12:707–708. Liu J, Wang F (2017) Role of neuroinflammation 43 in amyotrophic lateral sclerosis triggers nu- Zhang J, Liu Y, Liu X, Li S, Cheng C, Chen S, Le in amyotrophic lateral sclerosis: cellular mech- clear factor kB-mediated pathogenic pathways. W (2018) Dynamic changes of CX3CL1/ anisms and therapeutic implications. Front J Exp Med 208:2429–2447. CX3CR1 axis during microglial activation Immunol 8:1005. Tokuda E, Brännström T, Andersen PM, Marklund and motor neuron loss in the spinal cord of Massenzio F, Peña-Altamira E, Petralla S, Virgili SL (2016) Low autophagy capacity implicated ALS mouse model. Transl Neurodegener M,ZuccheriG,MitiA,PolazziE,MengoniI, in motor system vulnerability to mutant 7:35.