title: Immune response in peripheral axons delays disease progression in SOD1G93Amice.
abstract: Increasing evidence suggests that the immune system has a beneficial role in the progression of amyotrophic lateral sclerosis (ALS) although the mechanism remains unclear. Recently, we demonstrated that motor neurons (MNs) of C57SOD1G93Amice with slow disease progression activate molecules classically involved in the cross-talk with the immune system. This happens a lot less in 129SvSOD1G93Amice which, while expressing the same amount of transgene, had faster disease progression and earlier axonal damage. The present study investigated whether and how the immune response is involved in the preservation of motor axons in the mouse model of familial ALS with a more benign disease course.
  
  
  
  First, the extent of axonal damage, Schwann cell proliferation, and neuromuscular junction (NMJ) denervation were compared between the two ALS mouse models at the disease onset. Then, we compared the expression levels of different immune molecules, the morphology of myelin sheaths, and the presence of blood-derived immune cell infiltrates in the sciatic nerve of the two SOD1G93A mouse strains using immunohistochemical, immunoblot, quantitative reverse transcription PCR, and rotating-polarization Coherent Anti-Stokes Raman Scattering techniques.
  
  
  
  Muscle denervation, axonal dysregulation, and myelin disruption together with reduced Schwann cell proliferation are prominent in 129SvSOD1G93Acompared to C57SOD1G93Amice at the disease onset, and this correlates with a faster disease progression in the first strain. On the contrary, a striking increase of immune molecules such as CCL2, MHCI, and C3 was seen in sciatic nerves of slow progressor C57SOD1G93Amice and this was accompanied by heavy infiltration of CD8+T lymphocytes and macrophages. These phenomena were not detectable in the peripheral nervous system of fast-progressing mice.
  
  
  
  These data show for the first time that damaged MNs in SOD1-related ALS actively recruit immune cells in the peripheral nervous system to delay muscle denervation and prolong the lifespan. On the contrary, the lack of this response has a negative impact on the disease course.
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy. giovanni.nardo@marionegri.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Nardo
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Trolese
authors.affiliation: NEST, Scuola Normale Superiore, Piazza San Silvestro 12, I-56127, Pisa, Italy.|Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro 12, I-56127, Pisa, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: de Vito
authors.affiliation: NEST, Scuola Normale Superiore, Piazza San Silvestro 12, I-56127, Pisa, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cecchi
authors.affiliation: Neuropathology Unit, Department of Neurology, INSPE, San Raffaele Scientific Institute, Dibit II, Via Olgettina 48, 20132, Milan, Italy.
authors.forename: Nilo
authors.initials: N
authors.lastname: Riva
authors.affiliation: Neuropathology Unit, Department of Neurology, INSPE, San Raffaele Scientific Institute, Dibit II, Via Olgettina 48, 20132, Milan, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Dina
authors.affiliation: Department of Neuroscience, Academic Neurology Unit, Faculty of Medicine, Dentistry and Health, Sheffield Institute for Translational Neuroscience, University of Sheffield, 385 Glossop Road, Sheffield, S10 2HQ, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Heath
authors.affiliation: Neuropathology Unit, Department of Neurology, INSPE, San Raffaele Scientific Institute, Dibit II, Via Olgettina 48, 20132, Milan, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.affiliation: Department of Neuroscience, Academic Neurology Unit, Faculty of Medicine, Dentistry and Health, Sheffield Institute for Translational Neuroscience, University of Sheffield, 385 Glossop Road, Sheffield, S10 2HQ, UK.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro 12, I-56127, Pisa, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Piazza
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy. caterina.bendotti@marionegri.it.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000235:genetics; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009121:Muscle Denervation; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009776:Obturator Nerve / Q000378:metabolism / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D016207:Cytokines; D009419:Nerve Tissue Proteins; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex
keywords: Amyotrophic lateral sclerosis; Immune system; Peripheral nervous system; SOD1G93A mice