Motor Neurons Pathology After Chronic Exposure to MPTP in Mice

  • Giorgio Vivacqua
  • Francesca Biagioni
  • Carla L. Busceti
  • Michela Ferrucci
  • Michele Madonna
  • Larisa Ryskalin
  • Shun Yu
  • Loredana D’Este
  • Francesco FornaiEmail author
Original Article


The neurotoxin 1-methyl,4-phenyl-1,2,3,6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism in rodents and primates. Among different administration protocols, continuous or chronic exposure to small amounts of MPTP is reported to better mimic cell pathology reminiscent of Parkinson’s disease (PD). Catecholamine neurons are the most sensitive to MPTP neurotoxicity; however, recent studies have found that MPTP alters the fine anatomy of the spinal cord including motor neurons, thus overlapping again with the spinal cord involvement documented in PD. In the present study, we demonstrate that chronic exposure to low amounts of MPTP (10 mg/kg daily, × 21 days) significantly reduces motor neurons in the ventral lumbar spinal cord while increasing α-synuclein immune-staining within the ventral horn. Spinal cord involvement in MPTP-treated mice extends to Calbindin D28 KDa immune-reactive neurons other than motor neurons within lamina VII. These results were obtained in the absence of significant reduction of dopaminergic cell bodies in the Substantia Nigra pars compacta, while a slight decrease was documented in striatal tyrosine hydroxylase immune-staining. Thus, the present study highlights neuropathological similarities between dopaminergic neurons and spinal motor neurons and supports the pathological involvement of spinal cord in PD and experimental MPTP-induced parkinsonism. Remarkably, the toxic threshold for motor neurons appears to be lower compared with nigral dopaminergic neurons following a chronic pattern of MPTP intoxication. This sharply contrasts with previous studies showing that MPTP intoxication produces comparable neuronal loss within spinal cord and Substantia Nigra.


Spinal cord Stereology, α-Synuclein Calbindin D28 KDa Chronic MPTP exposure 


Authors’ Contributions

Original draft preparation [Giorgio Vivacqua, Francesco Fornai]; animal treatments [Giorgio Vivacqua, Francesca Biagioni]; immune-histochemistry [Giorgio Vivacqua, Francesca Biagioni]; SDS Page Immune-blotting [Francesca Biagioni]; stereology [Carla L. Busceti]; anti-alpha-synuclein 2E3 and 3D5 primary antibodies set-up [Shun Yu]; data analysis [Giorgio Vivacqua, Francesca Biagioni, Carla L. Busceti, Michela Ferrucci]; animal care [Michele Madonna]; writing the paper and editing [Michela Ferrucci, Larisa Ryskalin, Loredana D’Este, Francesco Fornai]; conceptualization, intellectual content, and supervision [Francesco Fornai].

Funding Information

This study was funded by University La Sapienza Roma, Ateneo 2012–2015, and Ministero della Salute, Ricerca Corrente 2019.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. Alim MA, Ma QL, Takeda K, Aizawa T, Matsubara M, Nakamura M, Asada A, Saito T, Kaji H, Yoshii M, Hisanaga S, Uéda K (2004) Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein. J Alzheimers Dis 6:435–442PubMedCrossRefGoogle Scholar
  2. Alvarez FJ, Fyffe RE (2007) The continuing case for the Renshaw cell. J Physiol 584:31–45PubMedPubMedCentralCrossRefGoogle Scholar
  3. Battaglia G, Busceti CL, Pontarelli F, Biagioni F, Fornai F, Paparelli A, Bruno V, Ruggieri S, Nicoletti F (2003) Protective role of group-II metabotropic glutamate receptors against nigro-striatal degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Neuropharmacology 45:155–166PubMedCrossRefGoogle Scholar
  4. Battaglia G, Busceti CL, Molinaro G, Biagioni F, Storto M, Fornai F, Nicoletti F, Bruno V (2004) Endogenous activation of mGlu5 metabotropic glutamate receptors contributes to the development of nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. J Neurosci 24:828–835PubMedPubMedCentralCrossRefGoogle Scholar
  5. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306PubMedCrossRefGoogle Scholar
  6. Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K (2007) Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 113:421–429PubMedCrossRefGoogle Scholar
  7. Brownstone RM, Lancelin C (2018) Escape from homeostasis: spinal microcircuits and progression of amyotrophic lateral sclerosis. J Neurophysiol 119:1782–1794PubMedPubMedCentralCrossRefGoogle Scholar
  8. Chandra S, Gallardo G, Fernandez-Chacon R, Schlüter OM, Südhof TC (2005) Alpha-synuclein cooperates with CSP-alpha in preventing neurodegeneration. Cell 123:383-396.PubMedCrossRefGoogle Scholar
  9. Chang Q, Martin LJ (2009) Glycinergic innervation of motoneurons is deficient in amyotrophic lateral sclerosis mice: a quantitative confocal analysis. Am J Pathol 174:574–585PubMedPubMedCentralCrossRefGoogle Scholar
  10. Chiba K, Trevor A, Castagnoli NJr (1984) Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 120:574-578.PubMedCrossRefGoogle Scholar
  11. Cleren C, Yang L, Lorenzo B, Calingasan NY, Schomer A, Sireci A, Wille EJ, Beal MF (2008) Therapeutic effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of parkinsonism. J Neurochem 104:1613–1621PubMedCrossRefGoogle Scholar
  12. Del Tredici K, Braak H (2012) Spinal cord lesions in sporadic Parkinson’s disease. Acta Neuropathol 124:643–664PubMedCrossRefGoogle Scholar
  13. Ferrucci M, Biagioni F, Vivacqua G, Busceti CL, Bartalucci A, Soldani P, D'Este L, Fumagalli L, Fornai F (2013) The neurobiology of the spinal cord in experimental parkinsonism and Parkinson’s disease. Arch Ital Biol 151:219–234PubMedGoogle Scholar
  14. Ferrucci M, Lazzeri G, Flaibani M, Biagioni F, Cantini F, Madonna M, Bucci D, Limanaqi F, Soldani P, Fornai F (2018) In search for a gold-standard procedure to count motor neurons in the spinal cord. Histol Histopathol 33:1021–1046PubMedGoogle Scholar
  15. Fornai F, Vaglini F, Maggio R, Bonuccelli U, Corsini GU (1996) Excitatory amino acids and MPTP toxicity. Adv Neurol 69:167–176PubMedGoogle Scholar
  16. Fornai F, Vaglini F, Maggio R, Bonuccelli U, Corsini GU (1997a) Species differences in the role of excitatory amino acids in experimental parkinsonism. Neurosci Biobehav Rev 21:401–415PubMedCrossRefGoogle Scholar
  17. Fornai F, Alessandrì MG, Torracca MT, Bassi L, Corsini GU (1997b) Effects of noradrenergic lesions on MPTP/MPP+ kinetics and MPTP-induced nigrostriatal dopamine depletions. J Pharmacol Exp Ther 283:100–107PubMedGoogle Scholar
  18. Fornai F, Giorgi FS, Alessandrí MG, Giusiani M, Corsini GU (1999a) Effects of pretreatment with N-(2-chloroethyl)-N-ethyl-2- bromobenzylamine (DSP-4) on methamphetamine pharmacokinetics and striatal dopamine losses. J Neurochem 72:777–784PubMedCrossRefGoogle Scholar
  19. Fornai F, Chen K, Giorgi FS, Gesi M, Alessandri MG, Shih JC (1999b) Striatal dopamine metabolism in monoamine oxidase B-deficient mice: a brain dialysis study. J Neurochem 73:2434–2440PubMedCrossRefPubMedCentralGoogle Scholar
  20. Fornai F, Carrì MT, Ferri A, Paolucci E, Prisco S, Bernardi G, Rotilio G, Mercuri NB (2002) Resistance to striatal dopamine depletion induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice expressing human mutant Cu,Zn superoxide dismutase. Neurosci Lett 325:124-128.PubMedCrossRefGoogle Scholar
  21. Fornai F, Schlüter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL, Pontarelli F, Battaglia G, Pellegrini A, Nicoletti F, Ruggieri S, Paparelli A, Südhof TC (2005) Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha synuclein. Proc Natl Acad Sci U S A 102:3413–3418PubMedPubMedCentralCrossRefGoogle Scholar
  22. Fornai F, Lazzeri G, Bandettini Di Poggio A, Soldani P, De Blasi A, Nicoletti F, Ruggieri S, Paparelli A (2006) Convergent roles of alpha-synuclein, DA metabolism, and the ubiquitin-proteasome system in nigrostriatal toxicity. Ann N Y Acad Sci 1074:84–89PubMedCrossRefGoogle Scholar
  23. Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferrucci M, Manca ML, Lazzeri G, Spallone A, Bellio N, Lenzi P, Modugno N, Siciliano G, Isidoro C, Murri L, Ruggieri S, Paparelli A (2008a) Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 105:2052–2057PubMedPubMedCentralCrossRefGoogle Scholar
  24. Fornai F, Longone P, Ferrucci M, Lenzi P, Isidoro C, Ruggieri S, Paparelli A (2008b) Autophagy and amyotrophic lateral sclerosis: the multiple roles of lithium. Autophagy 4:527–530PubMedCrossRefGoogle Scholar
  25. Fyffe RE (1990) Evidence for separate morphological classes of Renshaw cells in the cat’s spinal cord. Brain Res 536:301–304PubMedCrossRefGoogle Scholar
  26. Gesi M, Soldani P, Giorgi FS, Santinami A, Bonaccorsi I, Fornai F (2000) The role of the locus coeruleus in the development of Parkinson’s disease. Neurosci Biobehav Rev 24:655–668PubMedCrossRefGoogle Scholar
  27. Gesi M, Santinami A, Ruffoli R, Conti G, Fornai F (2001) Novel aspects of dopamine oxidative metabolism (confounding outcomes take place of certainties). Pharmacol Toxicol 89:217–224PubMedCrossRefGoogle Scholar
  28. Gesi M, Lazzeri G, Ferrucci M, Pellegrini A, Lenzi P, Ruggieri S, Fornai F, Paparelli A (2006) Inclusion dynamics in PC12 is comparable between amphetamines and MPTP. Ann N Y Acad Sci 1074:315–319PubMedCrossRefGoogle Scholar
  29. Gibrat C, Saint-Pierre M, Bousquet M, Lévesque D, Rouillard C, Cicchetti F (2009) Differences between subacute and chronic MPTP mice models: investigation of dopaminergic neuronal degeneration and alpha-synuclein inclusions. J Neurochem 109:1469–1482PubMedCrossRefGoogle Scholar
  30. Giorgi FS, Bandettini di Poggio A, Battaglia G, Pellegrini A, Murri L, Ruggieri S, Paparelli A, Fornai F (2006) A short overview on the role of alpha-synuclein and proteasome in experimental models of Parkinson’s disease. J Neural Transm Suppl 70:105–109CrossRefGoogle Scholar
  31. Gundersen HJ, Jensen EB, Kiêu K, Nielsen J (1999) The efficiency of systematic sampling in stereology reconsidered. J Microsc 193:199–211PubMedCrossRefGoogle Scholar
  32. Heikkila RE, Sieber BA, Manzino L, Sonsalla PK (1989) Some features of the nigrostriatal dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse. Mol Chem Neuropathol 10:171–183PubMedCrossRefGoogle Scholar
  33. Henchcliffe C, Beal MF (2008) Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 4:600–609PubMedCrossRefGoogle Scholar
  34. Jackson-Lewis V, Przedborski S (2007) Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc 2:141–151PubMedCrossRefGoogle Scholar
  35. Jankowska E, Lindström S (1971) Morphological identification of Renshaw cells. Acta Physiol Scand 81:428–430PubMedCrossRefGoogle Scholar
  36. King MA, Scotty N, Klein RL, Meyer EM (2002) Particle detection, number estimation, and feature measurement in gene transfer studies: optical fractionator stereology integrated with digital image processing and analysis. Methods 28:293–299PubMedCrossRefGoogle Scholar
  37. Kühn K, Wellen S, Link N, Maskri L, Lubbert H, Stichel CC (2003) The mouse MPTP model: gene expression changes in dopaminergic neurons. Eur J Neurosci 17:1–12PubMedCrossRefGoogle Scholar
  38. Lazzeri G, Lenzi P, Busceti CL, Ferrucci M, Falleni A, Bruno V, Paparelli A, Fornai F (2007) Mechanisms involved in the formation of dopamine-induced intracellular bodies within striatal neurons. J Neurochem 101:1414–1427PubMedCrossRefGoogle Scholar
  39. Lesage S, Anheim M, Letournel F, Bousset L, Honoré A, Rozas N, Pieri L, Madiona K, Dürr A, Melki R, Verny C, Brice A, French Parkinson's Disease Genetics Study Group (2013) G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann Neurol 73:459–471PubMedCrossRefPubMedCentralGoogle Scholar
  40. Ludtmann MHR, Angelova PR, Horrocks MH, Choi ML, Rodrigues M, Baev AY, Berezhnov AV, Yao Z, Little D, Banushi B, Al-Menhali AS, Ranasinghe RT, Whiten DR, Yapom R, Dolt KS, Devine MJ, Gissen P, Kunath T, Jaganjac M, Pavlov EV, Klenerman D, Abramov AY, Gandhi S (2018) α-Synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease. Nat Commun 9:2293.Google Scholar
  41. Markey SP, Johannessen JN, Chiueh CC, Burns RS, Herkenham MA (1984) Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism. Nature 311:464–467PubMedCrossRefGoogle Scholar
  42. Martin LJ (2007) Transgenic mice with human mutant genes causing Parkinson’s disease and amyotrophic lateral sclerosis provide common insight into mechanisms of motor neuron selective vulnerability to degeneration. Rev Neurosci 18:115–136PubMedCrossRefGoogle Scholar
  43. Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, Price DL, Lee MK (2006) Parkinson’s disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci 26:41–50PubMedPubMedCentralCrossRefGoogle Scholar
  44. Martínez JH, Fuentes F, Vanasco V, Alvarez S, Alaimo A, Cassina A, Coluccio Leskow F, Velazquez F (2018) Alpha-synuclein mitochondrial interaction leads to irreversible translocation and complex I impairment. Arch Biochem Biophys 651:1–12PubMedCrossRefGoogle Scholar
  45. Masilamoni GJ, Smith Y (2018) Chronic MPTP administration regimen in monkeys: a model of dopaminergic and non-dopaminergic cell loss in Parkinson’s disease. J Neural Transm (Vienna) 125:337–363CrossRefGoogle Scholar
  46. Meredith GE, Totterdell S, Potashkin JA, Surmeier DJ (2008) Modelling PD pathogenesis in mice: advantages of a chronic MPTP protocol. Parkinsonism Relat Disord 14:S112–S115PubMedPubMedCentralCrossRefGoogle Scholar
  47. Muñoz-Manchado AB, Villadiego J, Romo-Madero S, Suárez-Luna N, Bermejo-Navas A, Rodríguez-Gómez JA, Garrido-Gil P, Labandeira-García JL, Echevarría M, López-Barneo J, Toledo-Aral JJ (2016) Chronic and progressive Parkinson’s disease MPTP model in adult and aged mice. J Neurochem 136:373–387PubMedCrossRefGoogle Scholar
  48. Najim al-Din AS, Wriekat A, Mubaidin A, Dasouki M, Hiari M (1994) Pallido-pyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor-Rakeb syndrome. Acta Neurol Scand 89:347–352PubMedCrossRefGoogle Scholar
  49. Natale G, Biagioni F, Vivacqua G, D'Este L, Fumagalli L, Fornai F (2013) The neurobiology of dysautonomia in Parkinson’s disease. Arch Ital Biol 151:203–218PubMedGoogle Scholar
  50. Natale G, Lenzi P, Lazzeri G, Falleni A, Biagioni F, Ryskalin L, Fornai F (2015) Compartment-dependent mitochondrial alterations in experimental ALS, the effects of mitophagy and mitochondriogenesis. Front Cell Neurosci 9:434PubMedPubMedCentralCrossRefGoogle Scholar
  51. Nielsen MS, Glud AN, Møller A, Mogensen P, Bender D, Sørensen JC, Doudet D, Bjarkam CR (2016) Continuous MPTP intoxication in the Göttingen minipig results in chronic parkinsonian deficits. Acta Neurobiol Exp (Wars) 76:199–211Google Scholar
  52. Pasquali L, Longone P, Isidoro C, Ruggieri S, Paparelli A, Fornai F (2009) Autophagy, lithium, and amyotrophic lateral sclerosis. Muscle Nerve 40:173–194PubMedCrossRefGoogle Scholar
  53. Paxinos G, Franklin KBJ (2004) The mouse brain in stereotaxic coordinates (2nd Edition). Academic Press, San DiegoGoogle Scholar
  54. Petroske E, Meredith GE, Callen S, Totterdell S, Lau YS (2001) Mouse model of parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neuroscience 106:589–601PubMedCrossRefGoogle Scholar
  55. Pinto de Souza C, Hamani C, Oliveira Souza C, Lopez Contreras WO, Dos Santos Ghilardi MG, Cury RG, Reis Barbosa E, Jacobsen Teixeira M, Talamoni Fonoff E (2017) Spinal cord stimulation improves gait in patients with Parkinson's disease previously treated with deep brain stimulation. Mov Disord 32:278–282PubMedCrossRefGoogle Scholar
  56. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE (2017) Parkinson disease. Nat Rev Dis Primers 3:17013PubMedCrossRefGoogle Scholar
  57. Purisai MG, McCormack AL, Langston WJ, Johnston LC, Di Monte DA (2005) Alpha-synuclein expression in the substantia nigra of MPTP-lesioned non-human primates. Neurobiol Dis 20:898–906PubMedCrossRefGoogle Scholar
  58. Raudino F, Leva S (2012) Involvement of the spinal cord in Parkinson’s disease. Int J Neurosci 122:1–8PubMedCrossRefGoogle Scholar
  59. Ruffoli R, Bartalucci A, Frati A, Fornai F (2015) Ultrastructural studies of ALS mitochondria connect altered function and permeability with defects of mitophagy and mitochondriogenesis. Front Cell Neurosci 9:341PubMedPubMedCentralCrossRefGoogle Scholar
  60. Ruffoli R, Biagioni F, Busceti CL, Gaglione A, Ryskalin L, Gambardella S, Frati A, Fornai F (2017) Neurons other than motor neurons in motor neuron disease. Histol Histopathol 32:1115–1123PubMedPubMedCentralGoogle Scholar
  61. Samantaray S, Knaryan VH, Guyton MK, Matzelle DD, Ray SK, Banik NL (2007) The parkinsonian neurotoxin rotenone activates calpain and caspase-3 leading to motoneurons degeneration in spinal cord of Lewis rats. Neuroscience 146:741–755PubMedPubMedCentralCrossRefGoogle Scholar
  62. Samantaray S, Butler JT, Ray SK, Banik NL (2008a) Extranigral neurodegeneration in Parkinson’s disease. Ann N Y Acad Sci 1139:331–336PubMedCrossRefGoogle Scholar
  63. Samantaray S, Knaryan VH, Butler JT, Ray SK, Banik NL (2008b) Spinal cord degeneration in C57BL/6N mice following induction of experimental parkinsonism with MPTP. J Neurochem 104:1309–1320PubMedCrossRefGoogle Scholar
  64. Samantaray S, Knaryan VH, Shields DC, Cox AA, Haque A, Banik NL (2015) Inhibition of calpain activation protects MPTP-induced nigral and spinal cord neurodegeneration, reduces inflammation, and improves gait dynamics in mice. Mol Neurobiol 52:1054–1066PubMedPubMedCentralCrossRefGoogle Scholar
  65. Sanchez-Guajardo V, Tentillier N, Romero-Ramos M (2015) The relation between α-synuclein and microglia in Parkinson’s disease: recent developments. Neuroscience 302:47–58PubMedCrossRefGoogle Scholar
  66. Schapira AH (2011) Mitochondrial pathology in Parkinson’s disease. Mt Sinai J Med 78:872–881PubMedCrossRefGoogle Scholar
  67. Schapira AHV, Chaudhuri KR, Jenner P (2017) Non-motor features of Parkinson disease. Nat Rev Neurosci 18:435–450PubMedCrossRefGoogle Scholar
  68. Schlüter OM, Fornai F, Alessandrí MG, Takamori S, Geppert M, Jahn R, Südhof TC (2003) Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. Neuroscience 118:985–1002PubMedCrossRefGoogle Scholar
  69. Shepherd KR, Lee ES, Schmued L, Jiao Y, Ali SF, Oriaku ET, Lamango NS, Soliman KF, Charlton CG (2006) The potentiating effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on paraquat-induced neurochemical and behavioral changes in mice. Pharmacol Biochem Behav 83:349–359PubMedCrossRefGoogle Scholar
  70. Sonsalla PK, Heikkila RE (1986) The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice. Eur J Pharmacol 129:339–345PubMedCrossRefGoogle Scholar
  71. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedCrossRefGoogle Scholar
  72. Surmeier DJ, Obeso JA, Halliday GM (2017) Parkinson’s disease is not simply a prion disorder. J Neurosci 37:9799–9807PubMedPubMedCentralCrossRefGoogle Scholar
  73. Tong J, Hornykiewicz O, Kish SJ (2006) Inverse relationship between brain noradrenaline level and dopamine loss in Parkinson disease: a possible neuroprotective role for noradrenaline. Arch Neurol 63:1724–1728PubMedCrossRefGoogle Scholar
  74. Tretiakoff C (1919) Contributions a l’etude de l’anatomie pathologique du locus niger de soemmering avec quelques deductions relatives a la pathogenie des troubles de tonus musculaire et de la maladie de Parkinson. (Thesis, Paris).Google Scholar
  75. Trist BG, Davies KM, Cottam V, Genoud S, Ortega R, Roudeau S, Carmona A, De Silva K, Wasinger V, Lewis SJG, Sachdev P, Smith B, Troakes C, Vance C, Shaw C, Al-Sarraj S, Ball HJ, Halliday GM, Hare DJ, Double KL (2017) Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated with neuronal loss in Parkinson’s disease brain. Acta Neuropathol 134:113–127PubMedCrossRefGoogle Scholar
  76. Trojanowski JQ, Ishihara T, Higuchi M, Yoshiyama Y, Hong M, Zhang B, Forman MS, Zhukareva V, Lee VM (2002) Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam. Exp Neurol 176:1–11PubMedCrossRefGoogle Scholar
  77. Vivacqua G, Yin JJ, Casini A, Li X, Li YH, D’Este L, Chan P, Renda TG, Yu S (2009) Immunolocalization of alpha-synuclein in the rat spinal cord by two novel monoclonal antibodies. Neuroscience 158:1478–1487PubMedCrossRefGoogle Scholar
  78. Vivacqua G, Casini A, Vaccaro R, Fornai F, Yu S, D’Este L (2011a) Different sub-cellular localization of alpha-synuclein in the C57BL/6J mouse’s central nervous system by two novel monoclonal antibodies. J Chem Neuroanat 41:97–110PubMedCrossRefGoogle Scholar
  79. Vivacqua G, Casini A, Vaccaro R, Parisi Salvi E, Pasquali L, Fornai F, Yu S, D’Este L (2011b) Spinal cord and parkinsonism: neuromorphological evidences in humans and experimental studies. J Chem Neuroanat 42:327–340PubMedCrossRefGoogle Scholar
  80. Vivacqua G, Biagioni F, Yu S, Casini A, Bucci D, D'Este L, Fornai F (2012) Loss of spinal motor neurons and alteration of alpha-synuclein immunostaining in MPTP induced Parkinsonism in mice. J Chem Neuroanat 44:76–85PubMedCrossRefPubMedCentralGoogle Scholar
  81. West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482–497PubMedCrossRefPubMedCentralGoogle Scholar
  82. Wootz H, Fitzsimons-Kantamneni E, Larhammar M, Rotterman TM, Enjin A, Patra K, André E, Van Zundert B, Kullander K, Alvarez FJ (2013) Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model. J Comp Neurol 521:1449–1469PubMedPubMedCentralCrossRefGoogle Scholar
  83. Yeh TS, Huang YP, Wang HI, Pan SL (2016) Spinal cord injury and Parkinson’s disease: a population-based, propensity score-matched, longitudinal follow-up study. Spinal Cord 54:1215–1219PubMedCrossRefGoogle Scholar
  84. Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, Uèda K, Chan P (2007) Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody. Neuroscience 145:539–555PubMedCrossRefGoogle Scholar
  85. Zarow C, Lyness SA, Mortimer JA, Chui HC (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantianigra in Alzheimer and Parkinson diseases. Arch Neurol 60:337–341PubMedCrossRefGoogle Scholar
  86. Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, Vogel H, Steinberg GK, Edwards MS, Li G, Duncan JA 3rd, Cheshier SH, Shuer LM, Chang EF, Grant GA, Gephart MG, Barres BA (2016) Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89:37–53PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Giorgio Vivacqua
    • 1
    • 2
  • Francesca Biagioni
    • 3
  • Carla L. Busceti
    • 3
  • Michela Ferrucci
    • 4
  • Michele Madonna
    • 3
  • Larisa Ryskalin
    • 4
  • Shun Yu
    • 2
  • Loredana D’Este
    • 1
  • Francesco Fornai
    • 3
    • 4
    Email author
  1. 1.Department of Anatomy, Histology, Forensic Medicine and Locomotor SciencesRomeItaly
  2. 2.Department of NeurobiologyXuan Wu Hospital, Capital University of Medical SciencesBeijingChina
  3. 3.I.R.C.C.S. NeuromedPozzilliItaly
  4. 4.Department of Traslational Research and New Technologies in Medicine and SurgeryUniversity of PisaPisaItaly

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