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Effects of Astroglia on Motor Neurons in Spinal Muscular Atrophy

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Effects of Astroglia on Motor Neurons in Spinal Muscular Atrophy 8578 • The Journal of Neuroscience, September 6, 2017 • 37(36):8578–8580 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. Effects of Astroglia on Motor Neurons in Spinal Muscular Atrophy X Bert M. Verheijen Department of Translational Neuroscience, Brain 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). Astrocytes are increas- spinal cord, 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- neuron 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 homeostasis, 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 synapse 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 myelin and regulate In a recent study published in The cades, it is not clear how loss of SMN gives neuromuscular junction 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 astrocyte 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 Microglia Figure 1. Abnormal motor neuron–glia 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- receptor 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
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