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  • Review Article
  • Published:

Non-neuronal cells in amyotrophic lateral sclerosis — from pathogenesis to biomarkers

Nature Reviews Neurology volume 17, pages 333–348 (2021)Cite this article

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Abstract

The prevailing motor neuron-centric view of amyotrophic lateral sclerosis (ALS) pathogenesis could be an important factor in the failure to identify disease-modifying therapy for this neurodegenerative disorder. Non-neuronal cells have crucial homeostatic functions within the CNS and evidence of involvement of these cells in the pathophysiology of several neurodegenerative disorders, including ALS, is accumulating. Microglia and astrocytes, in crosstalk with peripheral immune cells, can exert both neuroprotective and adverse effects, resulting in a highly nuanced range of neuronal and non-neuronal cell interactions. This Review provides an overview of the diverse roles of non-neuronal cells in relation to the pathogenesis of ALS and the emerging potential of non-neuronal cell biomarkers to advance therapeutic development.

Key points

  • Accumulating evidence suggests that an exclusively motor neuron-centred model of pathogenesis in amyotrophic lateral sclerosis (ALS) is untenable, with important implications for therapeutic development strategies.

  • Brain-resident microglia, astrocytes and oligodendrocytes as well as peripheral immune cells all have vital functions in CNS homeostasis and physiology.

  • In multiple experimental models of ALS, non-neuronal cells seem to exert neurotoxic effects via both gain-of-function and loss-of-function mechanisms but also apparently show neuroprotective activity at certain disease stages.

  • Many of the hypotheses surrounding the roles of non-neuronal cells in ALS pathogenesis were developed using rodent models, some of which have limited relevance to the TDP43 neuropathological hallmark of human ALS.

  • Human induced pluripotent stem cells permit the investigation of non-neuronal cells carrying ALS-associated genetic mutations, but multicellular co-cultures might be needed to disentangle their nuanced interactions with motor neurons.

  • Human biofluid biomarkers derived from non-neuronal cells offer an important window into the in vivo pathological milieu and show potential as early markers of therapeutic response.

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Fig. 1: Pathophysiological roles of microglia, astrocytes and oligodendrocytes in amyotrophic lateral sclerosis.
Fig. 2: Pathophysiological roles of peripheral non-neuronal cells in amyotrophic lateral sclerosis.

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References

  1. Talbot, K., Feneberg, E., Scaber, J., Thompson, A. G. & Turner, M. R. Amyotrophic lateral sclerosis: the complex path to precision medicine. J. Neurol. 265, 2454–2462 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Al-Chalabi, A., van den Berg, L. H. & Veldink, J. Gene discovery in amyotrophic lateral sclerosis: implications for clinical management. Nat. Rev. Neurol. 13, 96–104 (2017).

    Article  CAS  PubMed  Google Scholar 

  3. Renton, A. E., Chio, A. & Traynor, B. J. State of play in amyotrophic lateral sclerosis genetics. Nat. Neurosci. 17, 17–23 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208–1211 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Brown, R. H. Jr & Al-Chalabi, A. Amyotrophic lateral sclerosis. N. Engl. J. Med. 377, 1602 (2017).

    Article  PubMed  Google Scholar 

  10. Thompson, A. G. et al. Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis. Ann. Neurol. 83, 258–268 (2018).

    Article  CAS  PubMed  Google Scholar 

  11. von Bartheld, C. S., Bahney, J. & Herculano-Houzel, S. The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J. Comp. Neurol. 524, 3865–3895 (2016).

    Article  Google Scholar 

  12. Jakel, S. & Dimou, L. Glial cells and their function in the adult brain: a journey through the history of their ablation. Front. Cell Neurosci. 11, 24 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Allen, N. J. & Lyons, D. A. Glia as architects of central nervous system formation and function. Science 362, 181–185 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Greenhalgh, A. D., David, S. & Bennett, F. C. Immune cell regulation of glia during CNS injury and disease. Nat. Rev. Neurosci. 21, 139–152 (2020).

    Article  CAS  PubMed  Google Scholar 

  15. Pelvig, D. P., Pakkenberg, H., Stark, A. K. & Pakkenberg, B. Neocortical glial cell numbers in human brains. Neurobiol. Aging 29, 1754–1762 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Alliot, F., Godin, I. & Pessac, B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res 117, 145–152 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bruttger, J. et al. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43, 92–106 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Kettenmann, H., Hanisch, U. K., Noda, M. & Verkhratsky, A. Physiology of microglia. Physiol. Rev. 91, 461–553 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Li, Q. & Barres, B. A. Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 18, 225–242 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Butovsky, O. & Weiner, H. L. Microglial signatures and their role in health and disease. Nat. Rev. Neurosci. 19, 622–635 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ransohoff, R. M. A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci. 19, 987–991 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Mantovani, A., Sica, A. & Locati, M. Macrophage polarization comes of age. Immunity 23, 344–346 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Hu, X. et al. Microglial and macrophage polarization-new prospects for brain repair. Nat. Rev. Neurol. 11, 56–64 (2015).

    Article  PubMed  Google Scholar 

  26. Ashford, B. A. et al. Review: microglia in motor neuron disease. Neuropathol. Appl. Neurobiol. 47, 179–197 (2021).

    Article  CAS  PubMed  Google Scholar 

  27. Tang, Y. & Le, W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol. Neurobiol. 53, 1181–1194 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Cherry, J. D., Olschowka, J. A. & O’Banion, M. K. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J. Neuroinflammation 11, 98 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Vass, K. & Lassmann, H. Intrathecal application of interferon gamma. Progressive appearance of MHC antigens within the rat nervous system. Am. J. Pathol. 137, 789–800 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Colonna, M. & Butovsky, O. Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35, 441–468 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Turner, M. R. et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol. Dis. 15, 601–609 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Zurcher, N. R. et al. Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: assessed with [(11)C]-PBR28. Neuroimage Clin. 7, 409–414 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Tondo, G. et al. 11C-PK11195 PET-based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis. Ann. Clin. Transl. Neurol. 7, 1513–1523 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Henkel, J. S. et al. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann. Neurol. 55, 221–235 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Brettschneider, J. et al. Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS ONE 7, e39216 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Brettschneider, J. et al. Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis. Acta Neuropathol. 123, 395–407 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Verkhratsky, A. & Nedergaard, M. Physiology of astroglia. Physiol. Rev. 98, 239–389 (2018).

    Article  CAS  PubMed  Google Scholar 

  38. Kriegstein, A. & Alvarez-Buylla, A. The glial nature of embryonic and adult neural stem cells. Annu. Rev. Neurosci. 32, 149–184 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vainchtein, I. D. & Molofsky, A. V. Astrocytes and microglia: in sickness and in health. Trends Neurosci. 43, 144–154 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zamanian, J. L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sofroniew, M. V. & Vinters, H. V. Astrocytes: biology and pathology. Acta Neuropathol. 119, 7–35 (2010).

    Article  PubMed  Google Scholar 

  42. Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Miller, S. J. Astrocyte heterogeneity in the adult central nervous system. Front. Cell Neurosci. 12, 401 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Clarke, L. E. et al. Normal aging induces A1-like astrocyte reactivity. Proc. Natl Acad. Sci. USA 115, E1896–E1905 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liddelow, S. A. & Barres, B. A. Reactive astrocytes: production, function, and therapeutic potential. Immunity 46, 957–967 (2017).

    Article  CAS  PubMed  Google Scholar 

  46. Kawamata, T., Akiyama, H., Yamada, T. & McGeer, P. L. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am. J. Pathol. 140, 691–707 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Tam, O. H. et al. Postmortem cortex samples identify distinct molecular subtypes of ALS: retrotransposon activation, oxidative stress, and activated glia. Cell Rep. 29, 1164–1177.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schiffer, D., Cordera, S., Cavalla, P. & Migheli, A. Reactive astrogliosis of the spinal cord in amyotrophic lateral sclerosis. J. Neurol. Sci. 139, 27–33 (1996).

    Article  PubMed  Google Scholar 

  49. Nagy, D., Kato, T. & Kushner, P. D. Reactive astrocytes are widespread in the cortical gray matter of amyotrophic lateral sclerosis. J. Neurosci. Res. 38, 336–347 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Kushner, P. D., Stephenson, D. T. & Wright, S. Reactive astrogliosis is widespread in the subcortical white matter of amyotrophic lateral sclerosis brain. J. Neuropathol. Exp. Neurol. 50, 263–277 (1991).

    Article  CAS  PubMed  Google Scholar 

  51. Johansson, A. et al. Evidence for astrocytosis in ALS demonstrated by [11C](L)-deprenyl-D2 PET. J. Neurol. Sci. 255, 17–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Valerio-Gomes, B., Guimaraes, D. M., Szczupak, D. & Lent, R. The absolute number of oligodendrocytes in the adult mouse brain. Front. Neuroanat. 12, 90 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bergles, D. E. & Richardson, W. D. Oligodendrocyte development and plasticity. Cold Spring Harb. Perspect. Biol. 8, a020453 (2015).

    Article  PubMed  Google Scholar 

  54. Philips, T. & Rothstein, J. D. Oligodendroglia: metabolic supporters of neurons. J. Clin. Invest. 127, 3271–3280 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Michalski, J. P. & Kothary, R. Oligodendrocytes in a nutshell. Front. Cell Neurosci. 9, 340 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Zhang, S. Z. et al. NG2 glia regulate brain innate immunity via TGF-beta2/TGFBR2 axis. BMC Med. 17, 204 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Nolan, M. et al. Quantitative patterns of motor cortex proteinopathy across ALS genotypes. Acta Neuropathol. Commun. 8, 98 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kierdorf, K., Masuda, T., Jordao, M. J. C. & Prinz, M. Macrophages at CNS interfaces: ontogeny and function in health and disease. Nat. Rev. Neurosci. 20, 547–562 (2019).

    Article  CAS  PubMed  Google Scholar 

  59. Prinz, M., Erny, D. & Hagemeyer, N. Ontogeny and homeostasis of CNS myeloid cells. Nat. Immunol. 18, 385–392 (2017).

    Article  CAS  PubMed  Google Scholar 

  60. Galea, I. et al. An antigen-specific pathway for CD8 T cells across the blood-brain barrier. J. Exp. Med. 204, 2023–2030 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hickey, W. F., Hsu, B. L. & Kimura, H. T-lymphocyte entry into the central nervous system. J. Neurosci. Res. 28, 254–260 (1991).

    Article  CAS  PubMed  Google Scholar 

  62. Engelhardt, B., Vajkoczy, P. & Weller, R. O. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18, 123–131 (2017).

    Article  CAS  PubMed  Google Scholar 

  63. Daar, A. S., Fuggle, S. V., Fabre, J. W., Ting, A. & Morris, P. J. The detailed distribution of MHC Class II antigens in normal human organs. Transplantation 38, 293–298 (1984).

    Article  CAS  PubMed  Google Scholar 

  64. Jarmin, S. J. et al. T cell receptor-induced phosphoinositide-3-kinase p110delta activity is required for T cell localization to antigenic tissue in mice. J. Clin. Invest. 118, 1154–1164 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. David, R. et al. T-cell receptor- and CD28-induced Vav1 activity is required for the accumulation of primed T cells into antigenic tissue. Blood 113, 3696–3705 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Garofalo, S. et al. Natural killer cells modulate motor neuron-immune cell cross talk in models of amyotrophic lateral sclerosis. Nat. Commun. 11, 1773 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775 (1994).

    Article  CAS  PubMed  Google Scholar 

  68. Philips, T. & Rothstein, J. D. Rodent models of amyotrophic lateral sclerosis. Curr. Protoc. Pharmacol. 69, 5.67.1–5.67.21 (2015).

    Article  Google Scholar 

  69. Turner, B. J. & Talbot, K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog. Neurobiol. 85, 94–134 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Hall, E. D., Oostveen, J. A. & Gurney, M. E. Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23, 249–256 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Alexianu, M. E., Kozovska, M. & Appel, S. H. Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57, 1282–1289 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Philips, T. & Robberecht, W. Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol. 10, 253–263 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Pramatarova, A., Laganière, J., Roussel, J., Brisebois, K. & Rouleau, G. A. Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J. Neurosci. 21, 3369–3374 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lino, M. M., Schneider, C. & Caroni, P. Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J. Neurosci. 22, 4825–4832 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang, L. et al. Restricted expression of mutant SOD1 in spinal motor neurons and interneurons induces motor neuron pathology. Neurobiol. Dis. 29, 400–408 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Jaarsma, D., Teuling, E., Haasdijk, E. D., De Zeeuw, C. I. & Hoogenraad, C. C. Neuron-specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice. J. Neurosci. 28, 2075–2088 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Beers, D. R. et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 103, 16021–16026 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ralph, G. S. et al. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat. Med. 11, 429–433 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Boillee, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389–1392 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Liao, B., Zhao, W., Beers, D. R., Henkel, J. S. & Appel, S. H. Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp. Neurol. 237, 147–152 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gravel, M. et al. IL-10 controls early microglial phenotypes and disease onset in ALS caused by misfolded superoxide dismutase 1. J. Neurosci. 36, 1031–1048 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Xiao, Q. et al. Mutant SOD1(G93A) microglia are more neurotoxic relative to wild-type microglia. J. Neurochem. 102, 2008–2019 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Zhao, W. et al. Extracellular mutant SOD1 induces microglial-mediated motoneuron injury. Glia 58, 231–243 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Weydt, P., Yuen, E. C., Ransom, B. R. & Moller, T. Increased cytotoxic potential of microglia from ALS-transgenic mice. Glia 48, 179–182 (2004).

    Article  PubMed  Google Scholar 

  85. Gowing, G., Dequen, F., Soucy, G. & Julien, J. P. Absence of tumor necrosis factor-alpha does not affect motor neuron disease caused by superoxide dismutase 1 mutations. J. Neurosci. 26, 11397–11402 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Meissner, F., Molawi, K. & Zychlinsky, A. Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc. Natl Acad. Sci. USA 107, 13046–13050 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Nguyen, M. D., Julien, J. P. & Rivest, S. Induction of proinflammatory molecules in mice with amyotrophic lateral sclerosis: no requirement for proapoptotic interleukin-1beta in neurodegeneration. Ann. Neurol. 50, 630–639 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Chiu, I. M. et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 4, 385–401 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M. & Baloh, R. H. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc. Natl Acad. Sci. USA 106, 18809–18814 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Jara, J. H. et al. MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology. J. Neuroinflammation 16, 196 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Zhao, W. et al. TDP-43 activates microglia through NF-kappaB and NLRP3 inflammasome. Exp. Neurol. 273, 24–35 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Deora, V. et al. The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins. Glia 68, 407–421 (2020).

    Article  PubMed  Google Scholar 

  93. Leal-Lasarte, M. M., Franco, J. M., Labrador-Garrido, A., Pozo, D. & Roodveldt, C. Extracellular TDP-43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase-3/IL-18 signaling in microglia. FASEB J. 31, 2797–2816 (2017).

    Article  CAS  PubMed  Google Scholar 

  94. Spiller, K. J. et al. Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy. Nat. Neurosci. 21, 329–340 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Svahn, A. J. et al. Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons. Acta Neuropathol. 136, 445–459 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Paolicelli, R. C. et al. TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron 95, 297–308.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. O’Rourke, J. G. et al. C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324–1329 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Lall, D. & Baloh, R. H. Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia. J. Clin. Invest. 127, 3250–3258 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  99. O’Rourke, J. G. et al. C9orf72 BAC transgenic mice display typical pathologic features of ALS/FTD. Neuron 88, 892–901 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Jiang, J. et al. Gain of toxicity from ALS/FTD-linked repeat expansions in c9orf72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs. Neuron 90, 535–550 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Peters, O. M. et al. Human C9ORF72 hexanucleotide expansion reproduces RNA foci and dipeptide repeat proteins but not neurodegeneration in BAC transgenic mice. Neuron 88, 902–909 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Mackenzie, I. R. et al. Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers. Acta Neuropathol. 130, 845–861 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Zhou, Q. et al. Active poly-GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model. EMBO Mol. Med. 12, e10919 (2020).

    CAS  PubMed  Google Scholar 

  104. Schludi, M. H. et al. Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss. Acta Neuropathol. 134, 241–254 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. LaClair, K. D. et al. Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS. Acta Neuropathol. 140, 121–142 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hao, Z. et al. Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR. Nat. Commun. 10, 2906 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Choi, S. Y. et al. C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo. Nat. Neurosci. 22, 851–862 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Zhang, Y. J. et al. Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nat. Med. 24, 1136–1142 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Koppers, M. et al. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann. Neurol. 78, 426–438 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Burberry, A. et al. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci. Transl. Med. 8, 347ra393 (2016).

    Article  CAS  Google Scholar 

  111. Lagier-Tourenne, C. et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc. Natl Acad. Sci. USA 110, E4530–E4539 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhu, Q. et al. Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72. Nat. Neurosci. 23, 615–624 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Rostalski, H. et al. Astrocytes and microglia as potential contributors to the pathogenesis of C9orf72 repeat expansion-associated FTLD and ALS. Front. Neurosci. 13, 486 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Yamanaka, K. et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat. Neurosci. 11, 251–253 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Gong, Y. H., Parsadanian, A. S., Andreeva, A., Snider, W. D. & Elliott, J. L. Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J. Neurosci. 20, 660–665 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wang, L., Gutmann, D. H. & Roos, R. P. Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice. Hum. Mol. Genet. 20, 286–293 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Lepore, A. C. et al. Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat. Neurosci. 11, 1294–1301 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Papadeas, S. T., Kraig, S. E., O’Banion, C., Lepore, A. C. & Maragakis, N. J. Astrocytes carrying the superoxide dismutase 1 (SOD1G93A) mutation induce wild-type motor neuron degeneration in vivo. Proc. Natl Acad. Sci. USA 108, 17803–17808 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Nagai, M. et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat. Neurosci. 10, 615–622 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Di Giorgio, F. P., Carrasco, M. A., Siao, M. C., Maniatis, T. & Eggan, K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat. Neurosci. 10, 608–614 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Di Giorgio, F. P., Boulting, G. L., Bobrowicz, S. & Eggan, K. C. Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 3, 637–648 (2008).

    Article  PubMed  CAS  Google Scholar 

  122. Marchetto, M. C. et al. Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3, 649–657 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Haidet-Phillips, A. M. et al. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat. Biotechnol. 29, 824–828 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Phatnani, H. P. et al. Intricate interplay between astrocytes and motor neurons in ALS. Proc. Natl Acad. Sci. USA 110, E756–E765 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ferraiuolo, L. et al. Dysregulation of astrocyte-motoneuron cross-talk in mutant superoxide dismutase 1-related amyotrophic lateral sclerosis. Brain 134, 2627–2641 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Vargas, M. R., Johnson, D. A., Sirkis, D. W., Messing, A. & Johnson, J. A. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J. Neurosci. 28, 13574–13581 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Pehar, M., Harlan, B. A., Killoy, K. M. & Vargas, M. R. Role and therapeutic potential of astrocytes in amyotrophic lateral sclerosis. Curr. Pharm. Des. 23, 5010–5021 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Yamanaka, K. & Komine, O. The multi-dimensional roles of astrocytes in ALS. Neurosci. Res. 126, 31–38 (2018).

    Article  CAS  PubMed  Google Scholar 

  129. Endo, F. et al. Astrocyte-derived TGF-β1 accelerates disease progression in ALS mice by interfering with the neuroprotective functions of microglia and T cells. Cell Rep. 11, 592–604 (2015).

    Article  CAS  PubMed  Google Scholar 

  130. Guttenplan, K. A. et al. Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model. Nat. Commun. 11, 3753 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Mishra, V. et al. Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow. Nat. Commun. 11, 5579 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Howland, D. S. et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc. Natl Acad. Sci. USA 99, 1604–1609 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bruijn, L. I. et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18, 327–338 (1997).

    Article  CAS  PubMed  Google Scholar 

  134. Ditsworth, D. et al. Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis. Acta Neuropathol. 133, 907–922 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Tong, J. et al. Expression of ALS-linked TDP-43 mutant in astrocytes causes non-cell-autonomous motor neuron death in rats. EMBO J. 32, 1917–1926 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Velebit, J. et al. Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism. Sci. Rep. 10, 6003 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Moujalled, D. et al. TDP-43 mutations causing amyotrophic lateral sclerosis are associated with altered expression of RNA-binding protein hnRNP K and affect the Nrf2 antioxidant pathway. Hum. Mol. Genet. 26, 1732–1746 (2017).

    Article  CAS  PubMed  Google Scholar 

  138. Rojas, F., Cortes, N., Abarzua, S., Dyrda, A. & van Zundert, B. Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress. Front. Cell Neurosci. 8, 24 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Huang, C. et al. Profiling the genes affected by pathogenic TDP-43 in astrocytes. J. Neurochem. 129, 932–939 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Bi, F. et al. Reactive astrocytes secrete lcn2 to promote neuron death. Proc. Natl Acad. Sci. USA 110, 4069–4074 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Iguchi, Y. et al. Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain 136, 1371–1382 (2013).

    Article  PubMed  Google Scholar 

  142. Wu, L. S., Cheng, W. C. & Shen, C. K. Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. J. Biol. Chem. 287, 27335–27344 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Yang, C. et al. Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 111, E1121–E1129 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. LaRocca, T. J., Mariani, A., Watkins, L. R. & Link, C. D. TDP-43 knockdown causes innate immune activation via protein kinase R in astrocytes. Neurobiol. Dis. 132, 104514 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kraemer, B. C. et al. Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol. 119, 409–419 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Chiang, P. M. et al. Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc. Natl Acad. Sci. USA 107, 16320–16324 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Serio, A. et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc. Natl Acad. Sci. USA 110, 4697–4702 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Haidet-Phillips, A. M. et al. Altered astrocytic expression of TDP-43 does not influence motor neuron survival. Exp. Neurol. 250, 250–259 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Smethurst, P. et al. Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis. Brain 143, 430–440 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Chew, J. et al. Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348, 1151–1154 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Zhang, Y. J. et al. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat. Neurosci. 19, 668–677 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Chew, J. et al. Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy. Mol. Neurodegener. 14, 9 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Meyer, K. et al. Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc. Natl Acad. Sci. USA 111, 829–832 (2014).

    Article  CAS  PubMed  Google Scholar 

  154. Hautbergue, G. M. et al. SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nat. Commun. 8, 16063 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Birger, A. et al. Human iPSC-derived astrocytes from ALS patients with mutated C9ORF72 show increased oxidative stress and neurotoxicity. EBioMedicine 50, 274–289 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Allen, S. P. et al. Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis. Brain 142, 586–605 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Allen, S. P. et al. C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis. Brain 142, 3771–3790 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Fomin, V. et al. The C9ORF72 gene, implicated in amyotrophic lateral sclerosis and frontotemporal dementia, encodes a protein that functions in control of endothelin and glutamate signaling. Mol. Cell Biol. 38, e00155-18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Varcianna, A. et al. Micro-RNAs secreted through astrocyte-derived extracellular vesicles cause neuronal network degeneration in C9orf72 ALS. EBioMedicine 40, 626–635 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Thompson, A. G. et al. Extracellular vesicles in neurodegenerative disease - pathogenesis to biomarkers. Nat. Rev. Neurol. 12, 346–357 (2016).

    Article  CAS  PubMed  Google Scholar 

  161. Zhao, C. et al. Mutant C9orf72 human iPSC-derived astrocytes cause non-cell autonomous motor neuron pathophysiology. Glia 68, 1046–1064 (2020).

    Article  PubMed  Google Scholar 

  162. Kang, S. H. et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat. Neurosci. 16, 571–579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Philips, T. et al. Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis. Brain 136, 471–482 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Yamanaka, K. et al. Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc. Natl Acad. Sci. USA 105, 7594–7599 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Ferraiuolo, L. et al. Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism. Proc. Natl Acad. Sci. USA 113, E6496–E6505 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Lee, Y. et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443–448 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Kim, S. et al. Myelin degeneration induced by mutant superoxide dismutase 1 accumulation promotes amyotrophic lateral sclerosis. Glia 67, 1910–1921 (2019).

    PubMed  Google Scholar 

  168. Sun, S. et al. Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS. Proc. Natl Acad. Sci. USA 112, E6993–E7002 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Livesey, M. R. et al. Maturation and electrophysiological properties of human pluripotent stem cell-derived oligodendrocytes. Stem Cell 34, 1040–1053 (2016).

    Article  CAS  Google Scholar 

  170. Butovsky, O. et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J. Clin. Invest. 122, 3063–3087 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Zhao, W. et al. Characterization of gene expression phenotype in amyotrophic lateral sclerosis monocytes. JAMA Neurol. 74, 677–685 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Du, Y. et al. Increased activation ability of monocytes from ALS patients. Exp. Neurol. 328, 113259 (2020).

    Article  CAS  PubMed  Google Scholar 

  173. Zondler, L. et al. Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol. 132, 391–411 (2016).

    Article  CAS  PubMed  Google Scholar 

  174. McCauley, M. E. et al. C9orf72 in myeloid cells suppresses STING-induced inflammation. Nature 585, 96–101 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Park, L. et al. Brain perivascular macrophages initiate the neurovascular dysfunction of Alzheimer Aβ peptides. Circ. Res. 121, 258–269 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Chiu, I. M. et al. T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc. Natl Acad. Sci. USA 105, 17913–17918 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Beers, D. R., Henkel, J. S., Zhao, W., Wang, J. & Appel, S. H. CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc. Natl Acad. Sci. USA 105, 15558–15563 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Beers, D. R. et al. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 134, 1293–1314 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Zhao, W., Beers, D. R., Liao, B., Henkel, J. S. & Appel, S. H. Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiol. Dis. 48, 418–428 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Beers, D. R. et al. ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight 2, e89530 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Henkel, J. S. et al. Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol. Med. 5, 64–79 (2013).

    Article  CAS  PubMed  Google Scholar 

  182. Sheean, R. K. et al. Association of regulatory T-cell expansion with progression of amyotrophic lateral sclerosis: a study of humans and a transgenic mouse model. JAMA Neurol. 75, 681–689 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Komine, O. et al. Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes. Cell Death Differ. 25, 2130–2146 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Nardo, G. et al. Counteracting roles of MHCI and CD8+ T cells in the peripheral and central nervous system of ALS SOD1(G93A) mice. Mol. Neurodegener. 13, 42 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Coque, E. et al. Cytotoxic CD8+ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons. Proc. Natl Acad. Sci. USA 116, 2312–2317 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Atanasio, A. et al. C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci. Rep. 6, 23204 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Zhao, W. et al. Immunosuppressive functions of M2 macrophages derived from iPSCs of patients with ALS and healthy controls. iScience 23, 101192 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Finkelstein, A. et al. Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS. PLoS ONE 6, e22374 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Murdock, B. J. et al. Correlation of peripheral immunity with rapid amyotrophic lateral sclerosis progression. JAMA Neurol. 74, 1446–1454 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Vijayakumar, U. G. et al. A systematic review of suggested molecular strata, biomarkers and their tissue sources in ALS. Front. Neurol. 10, 400 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Verber, N. & Shaw, P. J. Biomarkers in amyotrophic lateral sclerosis: a review of new developments. Curr. Opin. Neurol. 33, 662–668 (2020).

    Article  CAS  PubMed  Google Scholar 

  192. Varghese, A. M. et al. Chitotriosidase — a putative biomarker for sporadic amyotrophic lateral sclerosis. Clin. Proteom. 10, 19 (2013).

    Article  CAS  Google Scholar 

  193. Steinacker, P. et al. Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression. J. Neurol. Neurosurg. Psychiatry 89, 239–247 (2018).

    Article  PubMed  Google Scholar 

  194. Varghese, A. M. et al. Chitotriosidase, a biomarker of amyotrophic lateral sclerosis, accentuates neurodegeneration in spinal motor neurons through neuroinflammation. J. Neuroinflammation 17, 232 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Thompson, A. G. et al. CSF chitinase proteins in amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 90, 1215–1220 (2019).

    Article  PubMed  Google Scholar 

  196. Gray, E. et al. CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis. Ann. Clin. Transl. Neurol. 7, 1296–1306 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Oeckl, P. et al. Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase. J. Neurol. Neurosurg. Psychiatry 90, 4–10 (2019).

    Article  PubMed  Google Scholar 

  198. Gille, B. et al. Inflammatory markers in cerebrospinal fluid: independent prognostic biomarkers in amyotrophic lateral sclerosis? J. Neurol. Neurosurg. Psychiatry 90, 1338–1346 (2019).

    PubMed  Google Scholar 

  199. Illan-Gala, I. et al. CSF sAPPβ, YKL-40, and NfL along the ALS-FTD spectrum. Neurology 91, e1619–e1628 (2018).

    Article  PubMed  Google Scholar 

  200. Abu-Rumeileh, S. et al. Diagnostic-prognostic value and electrophysiological correlates of CSF biomarkers of neurodegeneration and neuroinflammation in amyotrophic lateral sclerosis. J. Neurol. 267, 1699–1708 (2020).

    Article  CAS  PubMed  Google Scholar 

  201. Gaur, N., Perner, C., Witte, O. W. & Grosskreutz, J. The chitinases as biomarkers for amyotrophic lateral sclerosis: signals from the CNS and beyond. Front. Neurol. 11, 377 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Castellani, R. J., Perry, G. & Smith, M. A. The role of novel chitin-like polysaccharides in Alzheimer disease. Neurotox. Res. 12, 269–274 (2007).

    Article  CAS  PubMed  Google Scholar 

  203. Vu, L. et al. Cross-sectional and longitudinal measures of chitinase proteins in amyotrophic lateral sclerosis and expression of CHI3L1 in activated astrocytes. J. Neurol. Neurosurg. Psychiatry 91, 350–358 (2020).

    Article  PubMed  Google Scholar 

  204. Andres-Benito, P. et al. YKL40 in sporadic amyotrophic lateral sclerosis: cerebrospinal fluid levels as a prognosis marker of disease progression. Aging 10, 2367–2382 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Chen, Y., Xia, K., Chen, L. & Fan, D. Increased interleukin-6 levels in the astrocyte-derived exosomes of sporadic amyotrophic lateral sclerosis patients. Front. Neurosci. 13, 574 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Henkel, J. S., Beers, D. R., Siklos, L. & Appel, S. H. The chemokine MCP-1 and the dendritic and myeloid cells it attracts are increased in the mSOD1 mouse model of ALS. Mol. Cell Neurosci. 31, 427–437 (2006).

    Article  CAS  PubMed  Google Scholar 

  207. Huang, F. et al. Longitudinal biomarkers in amyotrophic lateral sclerosis. Ann. Clin. Transl. Neurol. 7, 1103–1116 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Kuhle, J. et al. Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis. Eur. J. Neurol. 16, 771–774 (2009).

    Article  CAS  PubMed  Google Scholar 

  209. Guo, J., Yang, X., Gao, L. & Zang, D. Evaluating the levels of CSF and serum factors in ALS. Brain Behav. 7, e00637 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Lehnert, S. et al. Multicentre quality control evaluation of different biomarker candidates for amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 15, 344–350 (2014).

    Article  PubMed  Google Scholar 

  211. Nagata, T. et al. Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients. Neurol. Res. 29, 772–776 (2007).

    Article  CAS  PubMed  Google Scholar 

  212. Wilms, H. et al. Intrathecal synthesis of monocyte chemoattractant protein-1 (MCP-1) in amyotrophic lateral sclerosis: further evidence for microglial activation in neurodegeneration. J. Neuroimmunol. 144, 139–142 (2003).

    Article  CAS  PubMed  Google Scholar 

  213. Kiernan, M. C. et al. Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat. Rev. Neurol. 17, 104–118 (2021).

    Article  PubMed  Google Scholar 

  214. Mora, J. S. et al. Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial. Amyotroph. Lateral Scler. Frontotemporal Degener. 21, 5–14 (2020).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

B. F. V. is funded by the University of Oxford Clarendon Fund, St John’s College Oxford, the Oxford–Medical Research Council (MRC) Doctoral Training Partnership, and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. E. G. is supported by the Motor Neurone Disease Association. A. G. T. is supported by the MRC and Motor Neurone Disease Association Lady Edith Wolfson Clinician Scientist Fellowship. S. A. C. is supported through the Oxford Martin School. M. R. T. is supported by the Motor Neurone Disease Association. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care.

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  1. Oxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK

    Björn F. Vahsen, Elizabeth Gray, Alexander G. Thompson, Olaf Ansorge, Kevin Talbot & Martin R. Turner

  2. Department of Pharmacology, University of Oxford, Oxford, UK

    Daniel C. Anthony

  3. James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

    Sally A. Cowley

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B. F. V. researched data for the article and drafted the manuscript. B. F. V., E. G., S. A. C., K. T. and M. R. T. made substantial contributions to discussions of the content. E. G., A. G. T., O. A., D. C. A., S. A. C., K. T. and M. R. T. reviewed and edited the manuscript before submission.

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Vahsen, B.F., Gray, E., Thompson, A.G. et al. Non-neuronal cells in amyotrophic lateral sclerosis — from pathogenesis to biomarkers. Nat Rev Neurol 17, 333–348 (2021). https://doi.org/10.1038/s41582-021-00487-8

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