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Effects of Astroglia on Motor Neurons in Spinal Muscular Atrophy

Effects of Astroglia on Motor Neurons in Spinal Muscular Atrophy

8578 • The Journal of , September 6, 2017 • 37(36):8578–8580

Journal Club

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Effects of Astroglia on Motor in

X Bert M. Verheijen Department of Translational Neuroscience, Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands and Departmentof Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands Review of Martin et al.

Hereditary proximal spinal muscular at- that SMN is involved in several cellular system. For example, they influence syn- rophy (SMA), a severe neuromuscular processes, however, including pre-mRNA aptic communication and they support disorder and a leading genetic cause of in- splicing, transcription termination, RNA neuronal development and survival by fant death, is characterized by loss of mo- trafficking, local translation regulation and secreting multiple beneficial factors (e.g., tor neurons in the ventral horn of the stress granule formation (Monani, 2005; growth factors). are increas- , resulting in progressive muscle Burghes and Beattie, 2009; Singh et al., ingly recognized as key players in several atrophy and weakness (Lunn and Wang, 2017). Many studies on SMA focus exclu- neurodegenerative diseases, including motor 2008). SMA is an autosomal recessive disease sively on the perturbation of these pro- disease (Pekny et al., 2016). SMN- that is caused by homozygous disruptions of cesses in motor neurons as a result of deficient astrocytes show marked altera- the survival motor neuron 1 (SMN1) gene, SMN deficiency. However, accumulating tions and impairments, such as increased resulting in reduced levels of SMN protein evidence suggests that other cell types, in- expression of glial fibrillary acidic protein (Lefebvre et al., 1997). Although humans cluding non-neuronal cells like neuroglia, and shorter process length (which are in- have a second, highly homologous copy of also play important roles in SMA (Hamil- dicative of reactive astrocytosis), abnormal the SMN gene, named SMN2, it under- ton and Gillingwater, 2013). A convincing calcium , reduced neurotro- goes alternative splicing that truncates the argument for the involvement of non- phin production, and diminished support of transcript and therefore only produces motor neuron cells in SMA is the finding motor neuron formation in vitro small amounts of full-length SMN pro- that only systemic restoration of SMN lev- (McGivern et al., 2013; Zhou et al., 2016). tein. Nonetheless, SMN2 copy number els in SMA mouse models provides long- Notably, a selective increase of SMN in variation in patients is a major modifier of term rescue of the phenotype: increasing astrocytes increases life span in SMA mice, disease severity, because the number of SMN in neurons alone is less effective although it does not prevent motor neuron copies directly influences SMN protein (Hua et al., 2011; Martinez et al., 2012). death (Rindt et al., 2015). How astrocytes levels. Moreover, Schwann cells, the predomi- mediate these effects in SMA remains Although the genetic underpinnings of nant glial cells of the peripheral nervous unknown. SMA have been known for several de- system that produce and regulate In a recent study published in The cades, it is not clear how loss of SMN gives formation and Journal of Neuroscience, Martin et al. rise to SMA (Monani, 2005; Burghes and maintenance, show intrinsic defects in trans- (2017) revealed a novel aspect of Beattie, 2009). Previous work has indicated genic mouse models for SMA (Hunter et al., dysfunction in SMA. Through the use of 2014,2016). Therefore, insight into the contri- astrocyte-conditioned medium (ACM),

Received June 6, 2017; revised July 25, 2017; accepted July 27, 2017. bution of non-neuronal cells is crucial for a i.e., medium that had been incubated The author declares no competing financial interests. better understanding of SMA pathology, with SMN-deficient murine astrocytes, Correspondence should be addressed to Bert M. Verheijen, Department and it may lead to the identification of they observed motor neuron defects in of Translational Neuroscience, Brain Center Rudolf Magnus, University novel therapeutic targets. culture and identified a potential role Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands. E-mail: [email protected]. Astrocytes have also been found to for astrocyte-secreted monocyte che- DOI:10.1523/JNEUROSCI.1578-17.2017 contribute to SMA. These cells carry out moattractant protein 1 (CCL2/MCP1) Copyright © 2017 the authors 0270-6474/17/378578-03$15.00/0 numerous vital functions in the nervous in causing these defects. Verheijen • Journal Club J. Neurosci., September 6, 2017 • 37(36):8578–8580 • 8579

SMA Astrocyte

Astrocyte-secreted factors ↓ GFAP expression ↑

Pro-survival signaling? Excitotoxicity modulation? MCP1 ? Neuronal maturation?

Process lenght ↓ Neurite outgrowth ↓ Impaired Ca2+

? MCP1

Motor neuron marker expression ↓ Motor Neuron

SMA

Figure 1. Abnormal motor neuron– interactions in SMA. Astrocytes secrete factors to support neuron development and function. Reduced levels of secreted factors derived from cultures of murine astrocytes, specifically MCP1, induced motor neuron defects in culture. Glia and glia-secreted molecules could act as important drivers of SMA pathology. Astrocyte image based on original image from Cancer Research UK.

The authors isolated primary astro- experimental approach. Nevertheless, ELISA autocrine signaling on astrocytes. Con- cytes from spinal cord of both wild-type showed a substantial decrease of MCP1 pro- versely, addition of an anti-MCP1 neu- (WT) and SMA neonatal mice. These as- tein levels in SMA ACM compared with tralizing antibody to WT ACM impaired trocytes were cultured for 1 week, and me- WT ACM (Martin et al., 2017, their neurite outgrowth and reduced the ex- dium that had been on these cultures was Fig. 3). pression of motor neuron markers in pri- collected every 48 h. Collected ACM was MCP1 is a well-studied chemotactic mary mouse motor neurons as well as in then added to cultures of isolated primary protein that has been previously found to WT and SMA hiPSC motor neurons mouse motor neurons or motor neurons improve neuron survival and promote (Martin et al., 2017, their Figs. 7, 8). derived from human induced pluripotent neuronal activity and neurite outgrowth Overall, these results suggest that abnor- stem cells (hiPSCs). Compared with neu- in vitro. Both motor neurons and astro- mal levels of glia-secreted factors, including rons cultured in WT ACM, those grown in cytes have been shown to express CCR2, a the chemokine MCP1, in SMA contribute to medium from SMA astrocytes had signif- for MCP1 (see references in defects in cultured motor neurons (Fig. 1). icantly shorter neurites and lower expres- Martin et al., 2017). Martin et al. (2017) Martin et al. (2017) propose that the sion of motor neuron-specific expression measured MCP1 mRNA levels in WT and restoration of deficient astrocyte-secreted markers, indicating motor neuron loss SMA mouse spinal cords of different ages factors be explored as a therapeutic ap- (Martin et al., 2017, their Figs. 1, 2A,B). (Martin et al., 2017, their Fig. 4), and proach. Perhaps such an approach could hiPSC-motor neurons derived from SMA found reduced MCP1 levels in spinal complement therapies that aim to increase patient fibroblasts showed similar neurite cords of young mice with SMA. To deter- SMN protein levels (e.g., via gene therapy aberrations when cultured in SMA ACM mine whether MCP1 affects neuronal sur- and SMN2-targeting strategies; Foust et al., (Martin et al., 2017, their Fig. 2C,D). This vival and neurite outgrowth in culture, 2010; Corey, 2017; d’Ydewalle et al., 2017). indicated that SMA ACM negatively affects primary mouse motor neurons were sup- However, several questions should be ad- both WT and SMA motor neuron health in plemented with recombinant MCP1. The dressed before taking this step. vitro. addition of exogenous MCP1 stimulated First, no data on the purity of the as- To identify the factors present or lack- neurite outgrowth and increased the trocyte cultures is provided. Therefore, it ing in the SMA ACM that are responsible expression of a motor neuron marker is possible that other cells, including im- for these detrimental effects on motor (Martin et al., 2017, their Fig. 5). Simi- munoregulatory cells like microglia, were neurons, Martin et al. (2017) compared larly, MCP1 supplementation increased present in the astrocyte cultures that were the expression of 32 chemokines in WT neurite outgrowth in WT and SMA hiPSC- used. Reduced numbers or secretion of and SMA ACM. ELISAs were subse- derived motor neurons (Martin et al., 2017, MCP1 by such cells in the SMA condition quently performed to measure protein their Fig. 6). Importantly, the addition of may have contributed to the observed de- concentration of select chemokines. Of exogenous MCP1 to astrocytes alone did fects. Based on previous expression data, course, the astrocyte secretome contains not influence the effects of ACM on neu- it seems likely that microglia are an im- many more factors than these 32 chemo- rons, demonstrating that the effect on mo- portant source of MCP1 (Orre et al., 2014; kines, pointing out a drawback to this tor neurons is direct and is not due to Zhang et al., 2014, 2016). Future work 8580 • J. Neurosci., September 6, 2017 • 37(36):8578–8580 Verheijen • Journal Club could address this possibility by measur- neurological disorders. Upcoming studies Martin JE, Nguyen TT, Grunseich C, Nofziger JH, ing the expression of microglia marker will benefit from advances in the genera- Lee PR, Fields D, Fischbeck KH, Foran E Iba-1 in cultures or by purifying the astro- tion of different types of hiPSC-derived (2017) Decreased motor neuron support by SMA astrocytes due to diminished MCP1 cytes via fluorescence-activated cell sort- glial cells and gene-editing techniques to secretion. J Neurosci 37:5309–5318. CrossRef ing. If future therapies target particular accurately mimic patient cells in a nonx- Medline cell types, it will be important to accu- enogeneic setup. Nonetheless, any results Martinez TL, Kong L, Wang X, Osborne MA, rately identify the cells and mechanisms generated in vitro must ultimately be val- Crowder ME, Van Meerbeke JP, Xu X, Davis that mediate specific SMA-related defects. idated in in vivo experimental model sys- C, Wooley J, Goldhamer DJ, Lutz CM, Rich Yet, supplementing motor neurons with tems for SMA. It would be important to MM, Sumner CJ (2012) Survival motor neu- MCP1 remains a potential therapeutic confirm whether the restoration of glia- ron protein in motor neurons determines synaptic integrity in spinal muscular atrophy. option, regardless of the cellular source. secreted factors, such as MCP1, amelio- J Neurosci 32:8703–8715. CrossRef Medline Another unresolved question is how rates disease progression in SMA mice McGivern JV, Patitucci TN, Nord JA, Barabas MA, MCP1 achieves its advantageous down- before moving on to develop therapies. Stucky CL, Ebert AD (2013) Spinal muscular stream effects on motor neurons. It has atrophy astrocytes exhibit abnormal calcium been previously shown that MCP1 can be References regulation and reduced growth factor produc- Burghes AH, Beattie CE (2009) Spinal muscular tion. Glia 61:1418–1428. CrossRef Medline protective against HIV-1 transactivator atrophy: why do low levels of survival motor protein (Tat)-induced neurotoxicity, in a Monani UR (2005) Spinal muscular atrophy: a neuron protein make motor neurons sick? Nat deficiency in a ubiquitous protein; a motor CCR2-dependent manner (Yao et al., 2009). Rev Neurosci 10:597–609. CrossRef Medline neuron-specific disease. Neuron 48:885–896. Removal or blocking of CCR2 on motor Corey DR (2017) Nusinersen, an antisense oligo- CrossRef Medline neurons would reveal whether the effect nucleotide drug for spinal muscular atrophy. Orre M, Kamphuis W, Osborn LM, Melief J, of MCP1 is mediated by CCR2 signaling Nat Neurosci 20:497–499. CrossRef Medline Kooijman L, Huitinga I, Klooster J, Bossers K, d’Ydewalle C, Ramos DM, Pyles NJ, Ng SY, Gorz Hol EM (2014) Acute isolation and tran- or via other pathways. Through such M, Pilato CM, Ling K, Kong L, Ward AJ, pathways, MCP1 might, for example, in- scriptome characterization of cortical astro- Rubin LL, Rigo F, Bennett CF, Sumner CJ cytes and microglia from young and aged mice. hibit apoptosis or prevent excitotoxicity (2017) The antisense transcript SMN-AS1 Neurobiol Aging 35:1–14. CrossRef Medline in neurons (Madrigal et al., 2009). Dis- regulates SMN expression and is a novel ther- Pekny M, Pekna M, Messing A, Steinha¨user C, Lee secting the mechanisms in more detail apeutic target for spinal muscular atrophy. JM, Parpura V, Hol EM, Sofroniew MV, could result in novel therapeutic targets Neuron 93:66–79. CrossRef Medline Verkhratsky A (2016) Astrocytes: a central Foust KD, Wang X, McGovern VL, Braun L, element in neurological diseases. Acta Neuro- and enhanced therapeutic efficacy. Bevan AK, Haidet AM, Le TT, Morales PR, pathol 131:323–345. CrossRef Medline Finally, as pointed out by Martin et al. Rich MM, Burghes AH, Kaspar BK (2010) Rindt H, Feng Z, Mazzasette C, Glascock JJ, Val- (2017), modulating chemokine levels might Rescue of the spinal muscular atrophy pheno- divia D, Pyles N, Crawford TO, Swoboda KJ, type in a mouse model by early postnatal de- not be a viable approach in patients be- Patitucci TN, Ebert AD, Sumner CJ, Ko CP, livery of SMN. Nat Biotechnol 28:271–274. cause of the proinflammatory properties Lorson CL (2015) Astrocytes influence the CrossRef Medline of these molecules. In fact, there is evi- severity of spinal muscular atrophy. Hum Mol Hamilton G, Gillingwater TH (2013) Spinal Genet 24:4094–4102. CrossRef Medline dence that elevation of MCP1 levels and muscular atrophy: going beyond the motor Singh RN, Howell MD, Ottesen EW, Singh NN occur as SMA progresses (Rindt et al., neuron. Trends Mol Med 19:40–50. CrossRef (2017) Diverse role of survival motor neuron 2015). Astrocytic loss-of-function during Medline early development might shift toward a Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Ben- protein. Biochim Biophys Acta 1860:299–315. nett CF, Krainer AR (2011) Peripheral SMN CrossRef Medline toxic gain-of-function in later stages of Yao H, Peng F, Dhillon N, Callen S, Bokhari S, the disease, narrowing the therapeutic restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Stehno-Bittel L, Ahmad SO, Wang JQ, Buch S window of opportunity and the range of Nature 478:123–126. CrossRef Medline (2009) Involvement of TRPC channels in efficacy in patients. It is worth noting that Hunter G, Aghamaleky Sarvestany A, Roche SL, CCL2-mediated neuroprotection against tat the role of neuroinflammation and mi- Symes RC, Gillingwater TH (2014) SMN- toxicity. J Neurosci 29:1657–1669. CrossRef croglia, major immune effector cells in the dependent intrinsic defects in Schwann cells Medline , has been largely unex- in mouse models of spinal muscular atrophy. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze Hum Mol Genet 23:2235–2250. CrossRef AR, O’Keeffe S, Phatnani HP, Guarnieri P, plored in SMA (Rindt et al., 2015). It is Caneda C, Ruderisch N, Deng S, Liddelow SA, possible, for example, that abnormal syn- Medline Hunter G, Powis RA, Jones RA, Groen EJ, Shor- Zhang C, Daneman R, Maniatis T, Barres BA, aptic pruning by microglia contributes rock HK, Lane FM, Zheng Y, Sherman DL, Wu JQ (2014) AnRNA-sequencing transcrip- to the motor neuron deafferentation ob- Brophy PJ, Gillingwater TH (2016) Restora- tome and splicing database of glia, neurons, and served in SMA. Interactions of astrocyte- tion of SMN in Schwann cells reverses myeli- vascular cells of the cerebral cortex. J Neurosci secreted factors with other cells, including nation defects and improves neuromuscular 34:11929–11947. CrossRef Medline Schwann cells, microglia, and other astro- function in spinal muscular atrophy. Hum Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, Vogel H, Steinberg GK, cytes, should be investigated before seri- Mol Genet 25:2853–2861. CrossRef Medline Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont Edwards MS, Li G, Duncan JA 3rd, Cheshier ously considering the use of such factors O, Munnich A, Dreyfuss G, Melki J (1997) SH, Shuer LM, Chang EF, Grant GA, Gephart as a therapy. Correlation between severity and SMN pro- MG, Barres BA (2016) Purification and charac- In summary, glia-secreted factors ap- tein level in spinal muscular atrophy. Nat terization of progenitor and mature human pear to be an important contributor to Genet 16:265–269. CrossRef Medline astrocytes reveals transcriptional and func- motor neuron defects in SMA. Future Lunn MR, Wang CH (2008) Spinal muscular atro- tional differences with mouse. Neuron 89:37– 53. CrossRef Medline studies should aim to investigate the vari- phy. Lancet 371:2120–2133. CrossRef Medline Madrigal JL, Leza JC, Polak P, Kalinin S, Feinstein Zhou C, Feng Z, Ko CP (2016) Defects in moto- ety of secreted factors and the roles of DL (2009) Astrocyte-derived MCP-1 medi- neuron-astrocyte interactions in spinal muscu- these molecules in more detail. These ates neuroprotective effects of noradrenaline. lar atrophy. J Neurosci 36:2543–2553. CrossRef insights might also be relevant to other J Neurosci 29:263–267. CrossRef Medline Medline

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