Abstract
Motoneuron diseases (MNDs) represent a heterogeneous group of progressive paralytic disorders, mainly characterized by the loss of upper (corticospinal) motoneurons, lower (spinal) motoneurons or, often both. MNDs can occur from birth to adulthood and have a highly variable clinical presentation, even within gene-positive forms, suggesting the existence of environmental and genetic modifiers. A combination of cell autonomous and non-cell autonomous mechanisms contributes to motoneuron degeneration in MNDs, suggesting multifactorial pathogenic processes.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abati E, Citterio G, Bresolin N, Comi GP, Corti S (2020) Glial cells involvement in spinal muscular atrophy: could SMA be a neuroinflammatory disease? Neurobiol Dis 140:104870. https://doi.org/10.1016/j.nbd.2020.104870
Alberti S (2017) Phase separation in biology. Curr Biol 27:R1097–R1102. https://doi.org/10.1016/j.cub.2017.08.069
Al-Chalabi A, Fang F, Hanby MF, Leigh PN, Shaw CE, Ye W, Rijsdijk F (2010) An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry 81:1324–1326. https://doi.org/10.1136/jnnp.2010.207464
Alexianu ME, Kozovska M, Appel SH (2001) Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57:1282–1289
Almer G, Vukosavic S, Romero N, Przedborski S (2002) Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem 72:2415–2425. https://doi.org/10.1046/j.1471-4159.1999.0722415.x
Appel SH, Stewart SS, Appel V, Harati Y, Mietlowski W, Weiss W, Belendiuk GW (1988) A double-blind study of the effectiveness of cyclosporine in amyotrophic lateral sclerosis. Arch Neurol 45:381–386
Bahia El Idrissi N, Bosch S, Ramaglia V, Aronica E, Baas F, Troost D (2016) Complement activation at the motor end-plates in amyotrophic lateral sclerosis. J Neuroinflammation 13:72. https://doi.org/10.1186/s12974-016-0538-2
Banerjee R et al (2008) Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS One 3:e2740
Barbeito LH et al (2004) A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Brain Res Brain Res Rev 47:263–274
Beers DR, Appel SH (2019) Immune dysregulation in amyotrophic lateral sclerosis: mechanisms and emerging therapies. Lancet Neurol 18:211–220. https://doi.org/10.1016/S1474-4422(18)30394-6
Beers DR et al (2006) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 103:16021–16026. https://doi.org/10.1073/pnas.0607423103
Beers DR, Henkel JS, Zhao W, Wang J, Appel SH (2008) CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci U S A 105:15558–15563. https://doi.org/10.1073/pnas.0807419105
Beers DR et al (2011) 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. https://doi.org/10.1093/brain/awr074
Boillee S et al (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312:1389–1392
Branchereau P et al (2019) Relaxation of synaptic inhibitory events as a compensatory mechanism in fetal SOD spinal motor networks. elife 8:e51402. https://doi.org/10.7554/eLife.51402
Brannagan TH III (2010) Monomelic muscular atrophy. In: Rowland LP, Pedley TA (eds) Merritt’s neurology, 12th edn. Lippincott, Williams & Wilkins, Philadelphia, p 812
Brockington A et al (2013) Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity. Acta Neuropathol 125:95–109. https://doi.org/10.1007/s00401-012-1058-5
Butovsky O et al (2012) Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 122:3063–3087. https://doi.org/10.1172/JCI62636
Campbell AM, Williams ER, Barltrop D (1970) Motor neurone disease and exposure to lead. J Neurol Neurosurg Psychiatry 33:877–885. https://doi.org/10.1136/jnnp.33.6.877
Cassina P et al (2008) Mitochondrial dysfunction in S0D1(G93A)-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J Neurosci 28:4115–4122
Chio A, Benzi G, Dossena M, Mutani R, Mora G (2005) Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 128:472–476. https://doi.org/10.1093/brain/awh373
Chio A, Calvo A, Dossena M, Ghiglione P, Mutani R, Mora G (2009) ALS in Italian professional soccer players: the risk is still present and could be soccer-specific. Amyotroph Lateral Scler 10:205–209. https://doi.org/10.1080/17482960902721634
Chio A, Calvo A, Moglia C, Mazzini L, Mora G, Group Ps (2011) Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study. J Neurol Neurosurg Psychiatry 82:740–746. https://doi.org/10.1136/jnnp.2010.235952
Chiot A et al (2020) Modifying macrophages at the periphery has the capacity to change microglial reactivity and to extend ALS survival. Nat Neurosci 23:1339–1351. https://doi.org/10.1038/s41593-020-00718-z
Chiu IM et al (2008) T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci U S A 105:17913–17918. https://doi.org/10.1073/pnas.0804610105
Chiu IM et al (2009) Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc Natl Acad Sci U S A 106:20960–20965. https://doi.org/10.1073/pnas.0911405106
Chiu IM et al (2013) A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep 4:385–401. https://doi.org/10.1016/j.celrep.2013.06.018
Cirulli ET et al (2015) Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347:1436–1441. https://doi.org/10.1126/science.aaa3650
Ciryam P et al (2017) Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS. Proc Natl Acad Sci U S A 114:E3935–E3943. https://doi.org/10.1073/pnas.1613854114
Clark JA, Southam KA, Blizzard CA, King AE, Dickson TC (2016) Axonal degeneration, distal collateral branching and neuromuscular junction architecture alterations occur prior to symptom onset in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. J Chem Neuroanat 76:35–47. https://doi.org/10.1016/j.jchemneu.2016.03.003
Conforti L, Gilley J, Coleman MP (2014) Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat Rev Neurosci 15:394–409. https://doi.org/10.1038/nrn3680
Cook C, Petrucelli L (2019) Genetic convergence brings clarity to the enigmatic red line in ALS. Neuron 101:1057–1069. https://doi.org/10.1016/j.neuron.2019.02.032
Coque E et al (2019) Cytotoxic CD8(+) T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons. Proc Natl Acad Sci U S A 116:2312–2317. https://doi.org/10.1073/pnas.1815961116
Cottenie E et al (2014) Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. Am J Hum Genet 95:590–601. https://doi.org/10.1016/j.ajhg.2014.10.002
Couthouis J, Raphael AR, Daneshjou R, Gitler AD (2014) Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis. PLoS Genet 10:e1004704. https://doi.org/10.1371/journal.pgen.1004704
Cudkowicz ME et al (1997) Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol 41:210–221. https://doi.org/10.1002/ana.410410212
Cudkowicz ME, Shefner JM, Schoenfeld DA, Zhang H, Andreasson KI, Rothstein JD, Drachman DB (2006) Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol 60:22–31. https://doi.org/10.1002/ana.20903
D’Erchia AM et al (2017) Massive transcriptome sequencing of human spinal cord tissues provides new insights into motor neuron degeneration in ALS. Sci Rep 7:10046. https://doi.org/10.1038/s41598-017-10488-7
Dewan R et al (2021) Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Neuron 109:448–460 e444. https://doi.org/10.1016/j.neuron.2020.11.005
Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K (2007) Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10:608–614. https://doi.org/10.1038/nn1885
Di Giorgio FP, Boulting GL, Bobrowicz S, Eggan KC (2008) 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. https://doi.org/10.1016/j.stem.2008.09.017
Dobrowolny G et al (2008) Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab 8:425–436. https://doi.org/10.1016/j.cmet.2008.09.002
Dupuis L et al (2012) A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis. PLoS One 7:e37885. https://doi.org/10.1371/journal.pone.0037885
Elden AC et al (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075. https://doi.org/10.1038/nature09320
Elliott JL (2001) Cytokine upregulation in a murine model of familial amyotrophic lateral sclerosis. Brain Res Mol Brain Res 95:172–178
Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28:138–145. https://doi.org/10.1016/j.it.2007.01.005
Fatemi Y, Chakraborty R (2019) Acute flaccid myelitis: a clinical overview for 2019. Mayo Clin Proc 94:875–881. https://doi.org/10.1016/j.mayocp.2019.03.011
Feigin VL et al (2019) Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 18:459–480. https://doi.org/10.1016/S1474-4422(18)30499-X
Finkelstein A et al (2011) Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS. PLoS One 6:e22374. https://doi.org/10.1371/journal.pone.0022374
Fischer LR, Glass JD (2007) Axonal degeneration in motor neuron disease. Neurodegener Dis 4:431–442. https://doi.org/10.1159/000107704
Fischer LR et al (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 185:232–240. https://doi.org/10.1016/j.expneurol.2003.10.004
Fischer LR et al (2005) The WldS gene modestly prolongs survival in the SOD1G93A fALS mouse. Neurobiol Dis 19:293–300. https://doi.org/10.1016/j.nbd.2005.01.008
Fletcher EV et al (2017) Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy. Nat Neurosci 20:905–916. https://doi.org/10.1038/nn.4561
Fogh I et al (2014) A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Hum Mol Genet 23:2220–2231. https://doi.org/10.1093/hmg/ddt587
Fournier CN et al (2018) An open label study of a novel immunosuppression intervention for the treatment of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 19:242–249. https://doi.org/10.1080/21678421.2017.1421666
Frakes AE et al (2014) Microglia induce motor neuron death via the classical NF-kappaB pathway in amyotrophic lateral sclerosis. Neuron 81:1009–1023. https://doi.org/10.1016/j.neuron.2014.01.013
Freischmidt A et al (2015) Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci 18:631–636. https://doi.org/10.1038/nn.4000
Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P (2000) Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci 20:2534–2542
Fritz E et al (2013) Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability. J Neurophysiol 109:2803–2814. https://doi.org/10.1152/jn.00500.2012
Garofalo S et al (2020) Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis. Nat Commun 11:1773. https://doi.org/10.1038/s41467-020-15644-8
Gavrilina TO et al (2008) Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect. Hum Mol Genet 17:1063–1075. https://doi.org/10.1093/hmg/ddm379
GBD (2017) Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390:1345–1422. https://doi.org/10.1016/S0140-6736(17)32366-8
Gelfman S et al (2019) A new approach for rare variation collapsing on functional protein domains implicates specific genic regions in ALS. Genome Res 29:809–818. https://doi.org/10.1101/gr.243592.118
Gerbino V et al (2020) The loss of TBK1 kinase activity in motor neurons or in all cell types differentially impacts ALS disease progression in SOD1 mice. Neuron 106:789–805 e785. https://doi.org/10.1016/j.neuron.2020.03.005
Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35. https://doi.org/10.1038/nri978
Gordon PH et al (2004) Placebo-controlled phase I/II studies of minocycline in amyotrophic lateral sclerosis. Neurology 62:1845–1847
Gordon PH, Cheng B, Katz IB, Pinto M, Hays AP, Mitsumoto H, Rowland LP (2006a) The natural history of primary lateral sclerosis. Neurology 66:647–653. https://doi.org/10.1212/01.wnl.0000200962.94777.71
Gordon PH et al (2006b) Randomized controlled phase II trial of glatiramer acetate in ALS. Neurology 66:1117–1119
Gould TW et al (2006) Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS. J Neurosci 26:8774–8786. https://doi.org/10.1523/JNEUROSCI.2315-06.2006
Graber DJ, Hickey WF, Harris BT (2010) Progressive changes in microglia and macrophages in spinal cord and peripheral nerve in the transgenic rat model of amyotrophic lateral sclerosis. J Neuroinflammation 7:8–8. https://doi.org/10.1186/1742-2094-7-8
Graham AJ, Macdonald AM, Hawkes CH (1997) British motor neuron disease twin study. J Neurol Neurosurg Psychiatry 62:562–569. https://doi.org/10.1136/jnnp.62.6.562
Grohmann K et al (2001) Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat Genet 29:75–77
Guttenplan KA, Weigel MK, Adler DI, Couthouis J, Liddelow SA, Gitler AD, Barres BA (2020) Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model. Nat Commun 11:3753. https://doi.org/10.1038/s41467-020-17514-9
Haidet-Phillips AM et al (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29:824–828. https://doi.org/10.1038/nbt.1957
Hall ED, Oostveen JA, Gurney ME (1998) Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23:249–256
Hardiman O (2018) Global burden of motor neuron diseases: mind the gaps. Lancet Neurol 17:1030–1031. https://doi.org/10.1016/S1474-4422(18)30398-3
Harms MB, Baloh RH (2013) Clinical neurogenetics: amyotrophic lateral sclerosis. Neurol Clin 31:929–950. https://doi.org/10.1016/j.ncl.2013.05.003
Haukedal H, Freude K (2019) Implications of microglia in amyotrophic lateral sclerosis and frontotemporal dementia. J Mol Biol 431:1818–1829. https://doi.org/10.1016/j.jmb.2019.02.004
Henkel JS, Beers DR, Zhao W, Appel SH (2009) Microglia in ALS: the good, the bad, and the resting. J NeuroImmune Pharmacol 4:389–398. https://doi.org/10.1007/s11481-009-9171-5
Highley JR, Ince PG (2012) The neuropathology of the motor neuron diseases. In: Strong MJ (ed) Amyotrophic lateral sclerosis and the frontotemporal dementias, 1st edn. Oxford University Press, Oxford, pp xii, 413 p. https://doi.org/10.1093/med/9780199590674.003.0019
Hsiung GY et al (2012) Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 135:709–722. https://doi.org/10.1093/brain/awr354
Ikiz B et al (2015) The regulatory machinery of neurodegeneration in in vitro models of amyotrophic lateral sclerosis. Cell Rep 12:335–345. https://doi.org/10.1016/j.celrep.2015.06.019
Ince PG, Wharton SB (2007) Chapter 5: cytopathology of the motor neuron. Handb Clin Neurol 82:89–119. https://doi.org/10.1016/S0072-9752(07)80008-X
Ingre C, Roos PM, Piehl F, Kamel F, Fang F (2015) Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol 7:181–193. https://doi.org/10.2147/CLEP.S37505
IOM (2006) Amyotrophic lateral sclerosis in veterans: review of the scientific literature. The National Academies Press, Washington, DC. https://doi.org/10.17226/11757
Ito D, Suzuki N (2009) Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain 132:8–15. https://doi.org/10.1093/brain/awn216
Iyer CC et al (2015) Low levels of Survival Motor Neuron protein are sufficient for normal muscle function in the SMNDelta7 mouse model of SMA. Hum Mol Genet 24:6160–6173. https://doi.org/10.1093/hmg/ddv332
Jiang YM et al (2005) Gene expression profile of spinal motor neurons in sporadic amyotrophic lateral sclerosis. Ann Neurol 57:236–251. https://doi.org/10.1002/ana.20379
Johann S et al (2015) NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia 63:2260–2273. https://doi.org/10.1002/glia.22891
Johnson WG, Wigger HJ, Karp HR, Glaubiger LM, Rowland LP (1982) Juvenile spinal muscular atrophy: a new hexosaminidase deficiency phenotype. Ann Neurol 11:11–16. https://doi.org/10.1002/ana.410110103
Kang SH et al (2013) Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 16:571–579. https://doi.org/10.1038/nn.3357
Kanning KC, Kaplan A, Henderson CE (2010) Motor neuron diversity in development and disease. Annu Rev Neurosci 33:409–440. https://doi.org/10.1146/annurev.neuro.051508.135722
Kano O, Beers DR, Henkel JS, Appel SH (2012) Peripheral nerve inflammation in ALS mice: cause or consequence. Neurology 78:833–835. https://doi.org/10.1212/WNL.0b013e318249f776
Kaplan A et al (2014) Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration. Neuron 81:333–348. https://doi.org/10.1016/j.neuron.2013.12.009
Kariya S et al (2008) Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum Mol Genet 17:2552–2569
Kariya S, Mauricio R, Dai Y, Monani UR (2009) The neuroprotective factor Wld(s) fails to mitigate distal axonal and neuromuscular junction (NMJ) defects in mouse models of spinal muscular atrophy. Neurosci Lett 449:246–251. https://doi.org/10.1016/j.neulet.2008.10.107
Kaufmann P, De Vivo DC (2010) Spinal musclular atrophies of childhood. In: Rowland LP, Pedley TA (eds) Merrit’s neurology, 12th edn. Wolters Kluwer, Philadelphia, pp 810–811
Keller MF et al (2014) Genome-wide analysis of the heritability of amyotrophic lateral sclerosis. JAMA Neurol 71:1123–1134. https://doi.org/10.1001/jamaneurol.2014.1184
Keren-Shaul H et al (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169:1276–1290 e1217. https://doi.org/10.1016/j.cell.2017.05.018
Killian JM, Wilfong AA, Burnett L, Appel SH, Boland D (1994) Decremental motor responses to repetitive nerve stimulation in ALS. Muscle Nerve 17:747–754. https://doi.org/10.1002/mus.880170708
Kim WK, Liu X, Sandner J, Pasmantier M, Andrews J, Rowland LP, Mitsumoto H (2009) Study of 962 patients indicates progressive muscular atrophy is a form of ALS. Neurology 73:1686–1692. https://doi.org/10.1212/WNL.0b013e3181c1dea3
Kim G, Gautier O, Tassoni-Tsuchida E, Ma XR, Gitler AD (2020a) ALS genetics: gains, losses, and implications for future therapies. Neuron 108:822–842. https://doi.org/10.1016/j.neuron.2020.08.022
Kim JK et al (2020b) Muscle-specific SMN reduction reveals motor neuron-independent disease in spinal muscular atrophy models. J Clin Invest 130:1271–1287. https://doi.org/10.1172/JCI131989
Kline RA et al (2017) Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases. PLoS Genet 13:e1006680. https://doi.org/10.1371/journal.pgen.1006680
Kong L et al (2009) Impaired synaptic vesicle release and immaturity of neuromuscular junctions in spinal muscular atrophy mice. J Neurosci 29:842–851
Kosaka T et al (2012) Primary lateral sclerosis: upper-motor-predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration – immunohistochemical and biochemical analyses of TDP-43. Neuropathology 32:373–384. https://doi.org/10.1111/j.1440-1789.2011.01271.x
Kuzuhara S, Kokubo Y, Sasaki R, Narita Y, Yabana T, Hasegawa M, Iwatsubo T (2001) Familial amyotrophic lateral sclerosis and parkinsonism-dementia complex of the Kii Peninsula of Japan: clinical and neuropathological study and tau analysis. Ann Neurol 49:501–511
Lall D, Baloh RH (2017) Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia. J Clin Invest 127:3250–3258. https://doi.org/10.1172/JCI90607
Le Masson G, Przedborski S, Abbott LF (2014) A computational model of motor neuron degeneration. Neuron 83:975–988. https://doi.org/10.1016/j.neuron.2014.07.001
Lerman BJ et al (2012) Deletion of galectin-3 exacerbates microglial activation and accelerates disease progression and demise in a SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Brain Behav 2:563–575. https://doi.org/10.1002/brb3.75
Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237:1154–1162. https://doi.org/10.1126/science.3306916
Levine JB, Kong J, Nadler M, Xu Z (1999) Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS). Glia 28:215–224
Liddelow SA et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487. https://doi.org/10.1038/nature21029
Lillo P, Hodges JR (2009) Frontotemporal dementia and motor neurone disease: overlapping clinic-pathological disorders. J Clin Neurosci 16:1131–1135. https://doi.org/10.1016/j.jocn.2009.03.005
Liu Y et al (2016) C9orf72 BAC mouse model with motor deficits and neurodegenerative features of ALS/FTD. Neuron 90:521–534. https://doi.org/10.1016/j.neuron.2016.04.005
Lobsiger CS, Boillee S, McAlonis-Downes M, Khan AM, Feltri ML, Yamanaka K, Cleveland DW (2009) Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice. Proc Natl Acad Sci U S A 106:4465–4470. https://doi.org/10.1073/pnas.0813339106
Loeffler JP, Picchiarelli G, Dupuis L, Gonzalez De Aguilar JL (2016) The role of skeletal muscle in amyotrophic lateral sclerosis. Brain Pathol 26:227–236. https://doi.org/10.1111/bpa.12350
Logroscino G et al (2018) Global, regional, and national burden of motor neuron diseases 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 17:1083–1097. https://doi.org/10.1016/S1474-4422(18)30404-6
Mackenzie IRA, Briemberg H (2020) TDP-43 pathology in primary lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 21:52–58. https://doi.org/10.1080/21678421.2020.1790607
Majounie E et al (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11:323–330. https://doi.org/10.1016/S1474-4422(12)70043-1
Maniatis S et al (2019) Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis. Science 364:89–93. https://doi.org/10.1126/science.aav9776
Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH (2008) Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3:649–657. https://doi.org/10.1016/j.stem.2008.10.001
Martin LJ, Wong M (2020) Skeletal muscle-restricted expression of human SOD1 in transgenic mice causes a fatal ALS-like syndrome. Front Neurol 11:592851. https://doi.org/10.3389/fneur.2020.592851
Martin E, Cazenave W, Allain AE, Cattaert D, Branchereau P (2020) Implication of 5-HT in the dysregulation of chloride homeostasis in prenatal spinal motoneurons from the G93A mouse model of amyotrophic lateral sclerosis. Int J Mol Sci 21(3):1107. https://doi.org/10.3390/ijms21031107
Martineau E, Di Polo A, Vande Velde C, Robitaille R (2018) Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse model of ALS. elife 7:e41973. https://doi.org/10.7554/eLife.41973
Martineau E, Di Polo A, Vande Velde C, Robitaille R (2020) Sex-specific differences in motor-unit remodeling in a mouse model of ALS. eNeuro 7:ENEURO.0388-0319.2020. https://doi.org/10.1523/ENEURO.0388-19.2020
Mathys H et al (2017) Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep 21:366–380. https://doi.org/10.1016/j.celrep.2017.09.039
McAlary L, Plotkin SS, Yerbury JJ, Cashman NR (2019) Prion-like propagation of protein misfolding and aggregation in amyotrophic lateral sclerosis. Front Mol Neurosci 12:262. https://doi.org/10.3389/fnmol.2019.00262
McAndrew PE et al (1997) Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am J Hum Genet 60:1411–1422
McLaughlin RL et al (2017) Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. Nat Commun 8:14774. https://doi.org/10.1038/ncomms14774
Mentis GZ et al (2011) Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy. Neuron 69:453–467. https://doi.org/10.1016/j.neuron.2010.12.032
Meyer H, Weihl CC (2014) The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis. J Cell Sci 127:3877–3883. https://doi.org/10.1242/jcs.093831
Meyer K et al (2014) Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A 111:829–832. https://doi.org/10.1073/pnas.1314085111
Miller RG et al (2014) NP001 regulation of macrophage activation markers in ALS: a phase I clinical and biomarker study. Amyotroph Lateral Scler Frontotemporal Degener 15:601–609. https://doi.org/10.3109/21678421.2014.951940
Mishra V et al (2020) Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow. Nat Commun 11:5579. https://doi.org/10.1038/s41467-020-19177-y
Mitchell JD (1987) Heavy metals and trace elements in amyotrophic lateral sclerosis. Neurol Clin 5:43–60
Moisse K, Strong MJ (2006) Innate immunity in amyotrophic lateral sclerosis. Biochim Biophys Acta 1762:1083–1093. https://doi.org/10.1016/j.bbadis.2006.03.001
Murakami T et al (2015) ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron 88:678–690. https://doi.org/10.1016/j.neuron.2015.10.030
Murdock BJ, Zhou T, Kashlan SR, Little RJ, Goutman SA, Feldman EL (2017) Correlation of peripheral immunity with rapid amyotrophic lateral sclerosis progression. JAMA Neurol 74:1446–1454. https://doi.org/10.1001/jamaneurol.2017.2255
Nagai M, Kikuchi H, Przedborski S (2006) Experimental models of motor neuron diseases. In: Mitsumoto H, Przedborski S, Gordon PH (eds) Amyotrophic lateral sclerosis, Neurological disease and therapy, vol 78. Taylor & Francis, New York, pp 525–549
Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10:615–622. https://doi.org/10.1038/nn1876
Nagy D, Kato T, Kushner PD (1994) Reactive astrocytes are widespread in the cortical gray matter of amyotrophic lateral sclerosis. J Neurosci Res 38:336–347. https://doi.org/10.1002/jnr.490380312
Nardo G et al (2013) Transcriptomic indices of fast and slow disease progression in two mouse models of amyotrophic lateral sclerosis. Brain 136:3305–3332. https://doi.org/10.1093/brain/awt250
Nardo G et al (2018) Counteracting roles of MHCI and CD8(+) T cells in the peripheral and central nervous system of ALS SOD1(G93A) mice. Mol Neurodegener 13:42. https://doi.org/10.1186/s13024-018-0271-7
Naumann M et al (2019) Phenotypes and malignancy risk of different FUS mutations in genetic amyotrophic lateral sclerosis. Ann Clin Transl Neurol 6:2384–2394. https://doi.org/10.1002/acn3.50930
Neukomm LJ, Freeman MR (2014) Diverse cellular and molecular modes of axon degeneration. Trends Cell Biol 24:515–523. https://doi.org/10.1016/j.tcb.2014.04.003
Nguyen HP, Van Broeckhoven C, van der Zee J (2018) ALS genes in the genomic era and their implications for FTD. Trends Genet 34:404–423. https://doi.org/10.1016/j.tig.2018.03.001
Nijssen J, Comley LH, Hedlund E (2017) Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis. Acta Neuropathol 133:863–885. https://doi.org/10.1007/s00401-017-1708-8
Nikodemova M, Small AL, Smith SM, Mitchell GS, Watters JJ (2014) Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats. Neurobiol Dis 69:43–53. https://doi.org/10.1016/j.nbd.2013.11.009
Noristani HN et al (2015) Brca1 is expressed in human microglia and is dysregulated in human and animal model of ALS. Mol Neurodegener 10:34. https://doi.org/10.1186/s13024-015-0023-x
Pamphlett R (2010) Study of 962 patients indicates progressive muscular atrophy is a form of ALS. Neurology 74:1926. Author reply 1926-1927. https://doi.org/10.1212/WNL.0b013e3181e03b59
Pang SY et al (2017) Burden of rare variants in ALS genes influences survival in familial and sporadic ALS. Neurobiol Aging 58:238 e239–238 e215. https://doi.org/10.1016/j.neurobiolaging.2017.06.007
Patel A et al (2015) A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162:1066–1077. https://doi.org/10.1016/j.cell.2015.07.047
Pehar M et al (2004) Astrocytic production of nerve growth factor in motor neuron apoptosis: implications for amyotrophic lateral sclerosis. J Neurochem 89:464–473. https://doi.org/10.1111/j.1471-4159.2004.02357.x
Pehar M, Vargas MR, Cassina P, Barbeito AG, Beckman JS, Barbeito L (2005) Complexity of astrocyte-motor neuron interactions in amyotrophic lateral sclerosis. Neurodegener Dis 2:139–146
Phatnani HP et al (2013) Intricate interplay between astrocytes and motor neurons in ALS. Proc Natl Acad Sci U S A 110:E756–E765. https://doi.org/10.1073/pnas.1222361110
Philips T, Robberecht W (2011) Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol 10:253–263. https://doi.org/10.1016/S1474-4422(11)70015-1
Philips T et al (2013) Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis. Brain 136:471–482. https://doi.org/10.1093/brain/aws339
Plato CC et al (2003) Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam: changing incidence rates during the past 60 years. Am J Epidemiol 157:149–157. https://doi.org/10.1093/aje/kwf175
Poesen K, Van Damme P (2018) Diagnostic and prognostic performance of neurofilaments in ALS. Front Neurol 9:1167. https://doi.org/10.3389/fneur.2018.01167
Przedborski S (2017) Neurodegeneration. In: Ikezu T, Gendelman HE (eds) Neuroimmune pharmacology, 2nd edn. Springer, Cham, pp 345–354. https://doi.org/10.1007/978-3-319-44022-4_22
Pun S, Santos AF, Saxena S, Xu L, Caroni P (2006) Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci 9:408–419. https://doi.org/10.1038/nn1653
Ragagnin AMG, Shadfar S, Vidal M, Jamali MS, Atkin JD (2019) Motor neuron susceptibility in ALS/FTD. Front Neurosci 13:532. https://doi.org/10.3389/fnins.2019.00532
Rajabinejad M, Ranjbar S, Afshar Hezarkhani L, Salari F, Gorgin Karaji A, Rezaiemanesh A (2020) Regulatory T cells for amyotrophic lateral sclerosis/motor neuron disease: a clinical and preclinical systematic review. J Cell Physiol 235:5030–5040. https://doi.org/10.1002/jcp.29401
Ravits JM, La Spada AR (2009) ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology 73:805–811. https://doi.org/10.1212/WNL.0b013e3181b6bbbd
Re DB et al (2014) Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron 81:1001–1008. https://doi.org/10.1016/j.neuron.2014.01.011
Renton AE, Chio A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17:17–23. https://doi.org/10.1038/nn.3584
Rowland LP, Mitsumoto H, Przedborski S (2010) Amyotrophic lateral sclerosis, progressive musclar atrophy and primary lateral sclerosis. In: Rowland LP, Pedley TA (eds) Merritt’s neurology, 12th edn. Lippincott, Williams & Wilkins, Philadelphia, pp 802–808
Ryan MA, Heverin M, McLaughlin RL, Hardiman O (2019) Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol 76:1367–1374. https://doi.org/10.1001/jamaneurol.2019.2044
Saez-Atienzar S et al (2021) Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types. Sci Adv 7:eabd9036. https://doi.org/10.1126/sciadv.abd9036
Schaefer AM, Sanes JR, Lichtman JW (2005) A compensatory subpopulation of motor neurons in a mouse model of amyotrophic lateral sclerosis. J Comp Neurol 490:209–219. https://doi.org/10.1002/cne.20620
Schiffer D, Cordera S, Cavalla P, Migheli A (1996) Reactive astrogliosis of the spinal cord in amyotrophic lateral sclerosis. J Neurol Sci 139:27–33
Schon EA, Przedborski S (2011) Mitochondria: the next (neurode)generation. Neuron 70:1033–1053. https://doi.org/10.1016/j.neuron.2011.06.003
Schutz B (2005) Imbalanced excitatory to inhibitory synaptic input precedes motor neuron degeneration in an animal model of amyotrophic lateral sclerosis. Neurobiol Dis 20:131–140. https://doi.org/10.1016/j.nbd.2005.02.006
Sharma A et al (2016) ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat Commun 7:10465. https://doi.org/10.1038/ncomms10465
Shribman S, Reid E, Crosby AH, Houlden H, Warner TT (2019) Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches. Lancet Neurol 18:1136–1146. https://doi.org/10.1016/S1474-4422(19)30235-2
Silani V, Corcia P, Harms MB, Rouleau G, Siddique T, Ticozzi N (2020) Genetics of primary lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 21:28–34. https://doi.org/10.1080/21678421.2020.1837177
Simon CM et al (2017) Converging mechanisms of p53 activation drive motor neuron degeneration in spinal muscular atrophy. Cell Rep 21:3767–3780. https://doi.org/10.1016/j.celrep.2017.12.003
Spiller KJ, Cheung CJ, Restrepo CR, Kwong LK, Stieber AM, Trojanowski JQ, Lee VM (2016) Selective motor neuron resistance and recovery in a new inducible mouse model of TDP-43 proteinopathy. J Neurosci 36:7707–7717. https://doi.org/10.1523/JNEUROSCI.1457-16.2016
Srinivasan K et al (2016) Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses. Nat Commun 7:11295. https://doi.org/10.1038/ncomms11295
Swinnen B, Robberecht W (2014) The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol 10:661–670. https://doi.org/10.1038/nrneurol.2014.184
Tallon C, Russell KA, Sakhalkar S, Andrapallayal N, Farah MH (2016) Length-dependent axo-terminal degeneration at the neuromuscular synapses of type II muscle in SOD1 mice. Neuroscience 312:179–189. https://doi.org/10.1016/j.neuroscience.2015.11.018
Tanner CM, Goldman SM, Ross GW, Grate SJ (2014) The disease intersection of susceptibility and exposure: chemical exposures and neurodegenerative disease risk Alzheimers. Dement 10:S213–S225. https://doi.org/10.1016/j.jalz.2014.04.014
Taylor JP, Brown RH Jr, Cleveland DW (2016) Decoding ALS: from genes to mechanism. Nature 539:197–206. https://doi.org/10.1038/nature20413
Tisdale S, Pellizzoni L (2015) Disease mechanisms and therapeutic approaches in spinal muscular atrophy. J Neurosci 35:8691–8700. https://doi.org/10.1523/JNEUROSCI.0417-15.2015
Tiwari A, Hayward LJ (2005) Mutant SOD1 instability: implications for toxicity in amyotrophic lateral sclerosis. Neurodegener Dis 2:115–127. https://doi.org/10.1159/000089616
Toth RP, Atkin JD (2018) Dysfunction of optineurin in amyotrophic lateral sclerosis and glaucoma. Front Immunol 9:1017. https://doi.org/10.3389/fimmu.2018.01017
Towne C, Raoul C, Schneider BL, Aebischer P (2008) Systemic AAV6 delivery mediating RNA interference against SOD1: neuromuscular transduction does not alter disease progression in fALS mice. Mol Ther 16:1018–1025. https://doi.org/10.1038/mt.2008.73
Tremblay E, Martineau E, Robitaille R (2017) Opposite synaptic alterations at the neuromuscular junction in an ALS mouse model: when motor units matter. J Neurosci 37:8901–8918. https://doi.org/10.1523/JNEUROSCI.3090-16.2017
Tyzack GE et al (2017) A neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models. Nat Commun 8:1164. https://doi.org/10.1038/s41467-017-01283-z
van Blitterswijk M et al (2012a) Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum Mol Genet 21:3776–3784. https://doi.org/10.1093/hmg/dds199
van Blitterswijk M et al (2012b) Genetic overlap between apparently sporadic motor neuron diseases. PLoS One 7:e48983. https://doi.org/10.1371/journal.pone.0048983
Van Harten ACM, Phatnani H, Przedborski S (2021) Non-cell autonomous pathogenic mechanisms in amyotrophic lateral sclerosis. Trends Neurosci 44(8):658–668
Van Mossevelde S, van der Zee J, Cruts M, Van Broeckhoven C (2017a) Relationship between C9orf72 repeat size and clinical phenotype. Curr Opin Genet Dev 44:117–124. https://doi.org/10.1016/j.gde.2017.02.008
Van Mossevelde S et al (2017b) Clinical evidence of disease anticipation in families segregating a C9orf72 repeat expansion. JAMA Neurol 74:445–452. https://doi.org/10.1001/jamaneurol.2016.4847
van Rheenen W et al (2016) Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat Genet 48:1043–1048. https://doi.org/10.1038/ng.3622
Vande Velde C, Garcia ML, Yin X, Trapp BD, Cleveland DW (2004) The neuroprotective factor Wlds does not attenuate mutant SOD1-mediated motor neuron disease. NeuroMolecular Med 5:193–203. https://doi.org/10.1385/NMM:5:3:193
Veriepe J, Fossouo L, Parker JA (2015) Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons. Nat Commun 6:7319. https://doi.org/10.1038/ncomms8319
Vinsant S et al (2013) Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part II, results and discussion. Brain Behav 3:431–457. https://doi.org/10.1002/brb3.142
Vukojicic A et al (2019) The classical complement pathway mediates microglia-dependent remodeling of spinal motor circuits during development and in SMA. Cell Rep 29:3087–3100 e3087. https://doi.org/10.1016/j.celrep.2019.11.013
Wang M, Casey PJ (2016) Protein prenylation: unique fats make their mark on biology. Nat Rev Mol Cell Biol 17:110–122. https://doi.org/10.1038/nrm.2015.11
Weydt P, Yuen EC, Ransom BR, Moller T (2004) Increased cytotoxic potential of microglia from ALS-transgenic mice. Glia 48:179–182. https://doi.org/10.1002/glia.20062
Wingo TS, Cutler DJ, Yarab N, Kelly CM, Glass JD (2011) The heritability of amyotrophic lateral sclerosis in a clinically ascertained United States research registry. PLoS One 6:e27985. https://doi.org/10.1371/journal.pone.0027985
Wirth B, Brichta L, Schrank B, Lochmuller H, Blick S, Baasner A, Heller R (2006) Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Hum Genet 119:422–428. https://doi.org/10.1007/s00439-006-0156-7
Wootz H et al (2013) Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model. J Comp Neurol 521:1449–1469. https://doi.org/10.1002/cne.23266
Xiao Q, Zhao W, Beers DR, Yen AA, Xie W, Henkel JS, Appel SH (2007) Mutant SOD1(G93A) microglia are more neurotoxic relative to wild-type microglia. J Neurochem 102:2008–2019. https://doi.org/10.1111/j.1471-4159.2007.04677.x
Yamanaka K et al (2008a) Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc Natl Acad Sci U S A 105:7594–7599. https://doi.org/10.1073/pnas.0802556105
Yamanaka K et al (2008b) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11:251–253. https://doi.org/10.1038/nn2047
Young PE, Kum Jew S, Buckland ME, Pamphlett R, Suter CM (2017) Epigenetic differences between monozygotic twins discordant for amyotrophic lateral sclerosis (ALS) provide clues to disease pathogenesis. PLoS One 12:e0182638. https://doi.org/10.1371/journal.pone.0182638
Yuan JH et al (2017) Clinical diversity caused by novel IGHMBP2 variants. J Hum Genet 62:599–604. https://doi.org/10.1038/jhg.2017.15
Zhao W, Beers DR, Bell S, Wang J, Wen S, Baloh RH, Appel SH (2015) TDP-43 activates microglia through NF-kappaB and NLRP3 inflammasome. Exp Neurol 273:24–35. https://doi.org/10.1016/j.expneurol.2015.07.019
Acknowledgements
We thank Neil Shneider, Matthew Harms and George Mentis for their insightful comments on this chapter and Jennifer Heredia for her critical editing of this manuscript. S.P. is supported by the Department of Defense (W81XWH-13-0416), the National Institute of Health (NS107442, NS117583, NS111176, AG064596), and Project-ALS. F.L. is supported by grants from Cure SMA, Thompson Family Foundation Initiative (TFFI), Project-ALS and National Institute of Health (R21NS101575).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Lotti, F., Przedborski, S. (2022). Motoneuron Diseases. In: O'Donovan, M.J., Falgairolle, M. (eds) Vertebrate Motoneurons. Advances in Neurobiology, vol 28. Springer, Cham. https://doi.org/10.1007/978-3-031-07167-6_13
Download citation
DOI: https://doi.org/10.1007/978-3-031-07167-6_13
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-07166-9
Online ISBN: 978-3-031-07167-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)