Cellular and molecular pathophysiology in the progression of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder etiologically linked to the loss of substantia nigra (SN) dopaminergic neurons in the mid-brain. The etiopathology of sporadic PD is still unclear; however, the interaction of extrinsic and intrinsic factors may play a critical role in the onset and progression of the disease. Studies in animal models and human post-mortem tissue have identified distinct cellular and molecular changes in the diseased brain, suggesting complex interactions between different glial cell types and various molecular pathways. Small changes in the expression of specific genes in a single pathway or cell type possibly influence others at the cellular and system levels. These molecular and cellular signatures like neuroinflammation, oxidative stress, and autophagy have been observed in PD patients’ brain tissue. While the etiopathology of PD is still poorly understood, the interplay between glial cells and molecular events may play a crucial role in disease onset and progression.

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Fig. 1
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Data availability

Data will be available upon request after the manuscript is published.

Code availability

N/A.

References

  1. Abeliovich A, Gitler AD (2016) Defects in trafficking bridge Parkinson’s disease pathology and genetics. Nature 539:207–216

    PubMed  Article  PubMed Central  Google Scholar 

  2. Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10:1538–1543

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. Allen NJ, Eroglu C (2017) Cell Biology of Astrocyte-Synapse Interactions. Neuron 96:697–708

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. Alvarez JI, Katayama T, Prat A (2013) Glial influence on the blood brain barrier. Glia 61:1939–1958

    PubMed  PubMed Central  Article  Google Scholar 

  6. Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Med 10(Suppl):S18-25

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  7. Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt-Prigent A, Ruberg M, Hirsch EC, Agid Y (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12:25–31

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Arotcarena ML, Teil M, Dehay B (2019) Autophagy in synucleinopathy: the overwhelmed and defective machinery. Cells 8:565–589

    CAS  PubMed Central  Article  Google Scholar 

  9. Barres BA (2008) The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60:430–440

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. Barreto GE, Gonzalez J, Torres Y, Morales L (2011) Astrocytic-neuronal crosstalk: implications for neuroprotection from brain injury. Neurosci Res 71:107–113

    PubMed  Article  PubMed Central  Google Scholar 

  11. Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, Tsitsou-Kampeli A, Sarel A, Cahalon L, Schwartz M (2015) Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer’s disease pathology. Nat Commun 6:7967

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Bayraktar OA, Bartels T, Holmqvist S, Kleshchevnikov V, Martirosyan A, Polioudakis D, Ben Haim L, Young AMH, Batiuk MY, Prakash K et al (2020) Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map. Nat Neurosci 23:500–509

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 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 3:1301–1306

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR (2015) Oxidative stress and Parkinson’s disease. Front Neuroanat 9:91

    PubMed  PubMed Central  Google Scholar 

  15. Braak H, Rub U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna) 110:517–536

    CAS  Article  Google Scholar 

  16. Braak H, de Vos RA, Bohl J, Del Tredici K (2006) Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 396:67–72

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM et al (2009) Infiltration of CD4 + lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Investig 119:182–192

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Brooks J, Ding J, Simon-Sanchez J, Paisan-Ruiz C, Singleton AB, Scholz SW (2009) Parkin and PINK1 mutations in early-onset Parkinson’s disease: comprehensive screening in publicly available cases and control. J Med Genet 46:375–381

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C et al (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 357:1255–1261

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Cabezas R, Avila M, Gonzalez J, El-Bacha RS, Baez E, Garcia-Segura LM, Jurado Coronel JC, Capani F, Cardona-Gomez GP, Barreto GE (2014) Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease. Front Cell Neurosci 8:211

    PubMed  PubMed Central  Article  Google Scholar 

  21. Cerri S, Blandini F (2019) Role of autophagy in Parkinson’s disease. Curr Med Chem 26:3702–3718

    CAS  PubMed  Article  Google Scholar 

  22. Cerri S, Mus L, Blandini F (2019) Parkinson’s disease in women and men: what’s the difference? J Parkinsons Dis 9:501–515

    PubMed  PubMed Central  Article  Google Scholar 

  23. Chabot S, Charlet D, Wilson TL, Yong VW (2001) Cytokine production consequent to T cell–microglia interaction: the PMA/IFN gamma-treated U937 cells display similarities to human microglia. J Neurosci Methods 105:111–120

    CAS  PubMed  Article  Google Scholar 

  24. Choi YR, Kang SJ, Kim JM, Lee SJ, Jou I, Joe EH, Park SM (2015) FcgammaRIIB mediates the inhibitory effect of aggregated alpha-synuclein on microglial phagocytosis. Neurobiol Dis 83:90–99

    CAS  PubMed  Article  Google Scholar 

  25. Choi I, Zhang Y, Seegobin SP, Pruvost M, Wang Q, Purtell K, Zhang B, Yue Z (2020) Microglia clear neuron-released alpha-synuclein via selective autophagy and prevent neurodegeneration. Nat Commun 11:1386

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120:421–433

    CAS  PubMed  Article  Google Scholar 

  27. Chung WS, Welsh CA, Barres BA, Stevens B (2015) Do glia drive synaptic and cognitive impairment in disease? Nat Neurosci 18:1539–1545

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Cicchetti F, Brownell AL, Williams K, Chen YI, Livni E, Isacson O (2002) Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci 15:991–998

    CAS  PubMed  Article  Google Scholar 

  29. Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B (2011) RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12:560–567

    CAS  PubMed  Article  Google Scholar 

  30. Colombo E, Farina C (2016) Astrocytes: key regulators of neuroinflammation. Trends Immunol 37:608–620

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. Cox A, Capone M, Matzelle D, Vertegel A, Bredikhin M, Varma A, Haque A, Shields DC, Banik NL (2021) Nanoparticle-based estrogen delivery to spinal cord injury site reduces local parenchymal destruction and improves functional recovery. J Neurotrauma 38:342–352

  32. Croisier E, Moran LB, Dexter DT, Pearce RK, Graeber MB (2005) Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J Neuroinflammation 2:14

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. Cui H, Kong Y, Zhang H (2012) Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduct 2012:646354

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  34. Daher JP, Volpicelli-Daley LA, Blackburn JP, Moehle MS, West AB (2014) Abrogation of alpha-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc Natl Acad Sci USA 111:9289–9294

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. Dansokho C, Ait Ahmed D, Aid S, Toly-Ndour C, Chaigneau T, Calle V, Cagnard N, Holzenberger M, Piaggio E, Aucouturier P et al (2016) Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain 139:1237–1251

    PubMed  Article  PubMed Central  Google Scholar 

  36. De Biase LM, Schuebel KE, Fusfeld ZH, Jair K, Hawes IA, Cimbro R, Zhang HY, Liu QR, Shen H, Xi ZX et al (2017) Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia. Neuron 95:341–356 e346

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. De Lucia C, Rinchon A, Olmos-Alonso A, Riecken K, Fehse B, Boche D, Perry VH, Gomez-Nicola D (2016) Microglia regulate hippocampal neurogenesis during chronic neurodegeneration. Brain Behav Immun 55:179–190

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. Deas E, Wood NW, Plun-Favreau H (2011) Mitophagy and Parkinson’s disease: the PINK1-parkin link. Biochim Biophys Acta 1813:623–633

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Dias V, Junn E, Mouradian MM (2013) The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis 3:461–491

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Diaz-Aparicio I, Paris I, Sierra-Torre V, Plaza-Zabala A, Rodriguez-Iglesias N, Marquez-Ropero M, Beccari S, Huguet P, Abiega O, Alberdi E et al (2020) Microglia Actively Remodel Adult Hippocampal Neurogenesis through the Phagocytosis Secretome. J Neurosci 40:1453–1482

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62:649–671

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. Eng LF, Ghirnikar RS, Lee YL (2000) Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem Res 25:1439–1451

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. Ferreira SA, Romero-Ramos M (2018) Microglia response during Parkinson’s disease: alpha-synuclein intervention. Front Cell Neurosci 12:247

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. Filiano AJ, Gadani SP, Kipnis J (2017) How and why do T cells and their derived cytokines affect the injured and healthy brain? Nat Rev Neurosci 18:375–384

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK (2018) Reactive oxygen species in metabolic and inflammatory signaling. Circ Res 122:877–902

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Frost JL, Schafer DP (2016) Microglia: architects of the developing nervous system. Trends Cell Biol 26:587–597

    PubMed  PubMed Central  Article  Google Scholar 

  47. Fuzzati-Armentero MT, Cerri S, Blandini F (2019) Peripheral-central neuroimmune crosstalk in Parkinson’s disease: what do patients and animal models tell. Us? Front Neurol 10:232

    PubMed  Article  PubMed Central  Google Scholar 

  48. Gautier CA, Kitada T, Shen J (2008) Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci U S A 105:11364–11369

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Ge P, Dawson VL, Dawson TM (2020) PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson’s disease. Mol Neurodegener 15:20

    PubMed  PubMed Central  Article  Google Scholar 

  50. Gertig U, Hanisch UK (2014) Microglial diversity by responses and responders. Front Cell Neurosci 8:101

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. Glick D, Barth S, Macleod KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221:3–12

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Goetz CG (2011) The history of Parkinson’s disease: early clinical descriptions and neurological therapies. Cold Spring Harb Perspect Med 1:a008862

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK, Stevens MP, Freeman TC, Summers KM, McColl BW (2016) Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat Neurosci 19:504–516

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Guo M (2012) Drosophila as a model to study mitochondrial dysfunction in Parkinson’s disease. Cold Spring Harb Perspect Med 2:a009944

  55. Guo JD, Zhao X, Li Y, Li GR, Liu XL (2018) Damage to dopaminergic neurons by oxidative stress in Parkinson’s disease (Review). Int J Mol Med 41:1817–1825

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Halliday GM, Stevens CH (2011) Glia: initiators and progressors of pathology in Parkinson’s disease. Mov Disord 26:6–17

    PubMed  Article  PubMed Central  Google Scholar 

  57. Haque A, Samantaray S, Knaryan VH, Capone M, Hossain A, Matzelle D, Chandran R, Shields DC, Farrand AQ, Boger HA et al (2020) Calpain mediated expansion of CD4 + cytotoxic T cells in rodent models of Parkinson’s disease. Exp Neurol 330:113315

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Hauben E, Schwartz M (2003) Therapeutic vaccination for spinal cord injury: helping the body to cure itself. Trends Pharmacol Sci 24:7–12

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annual review of genetics 43:67–93

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Heithoff BP, George KK, Phares AN, Zuidhoek IA, Munoz-Ballester C, Robel S (2021) Astrocytes are necessary for blood-brain barrier maintenance in the adult mouse brain. 69:436–472

  61. Hirsch L, Jette N, Frolkis A, Steeves T, Pringsheim T (2016) The incidence of parkinson’s disease: a systematic review and meta-analysis. Neuroepidemiology 46:292–300

    PubMed  Article  PubMed Central  Google Scholar 

  62. Hoglinger GU, Lannuzel A, Khondiker ME, Michel PP, Duyckaerts C, Feger J, Champy P, Prigent A, Medja F, Lombes A et al (2005) The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy. J Neurochem 95:930–939

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. Huang X, Reynolds AD, Mosley RL, Gendelman HE (2009) CD 4 + T cells in the pathobiology of neurodegenerative disorders. J Neuroimmunol 211:3–15

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Hurn PD, Subramanian S, Parker SM, Afentoulis ME, Kaler LJ, Vandenbark AA, Offner H (2007) T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab 27:1798–1805

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Ibanez P, Lesage S, Janin S, Lohmann E, Durif F, Destee A, Bonnet AM, Brefel-Courbon C, Heath S, Zelenika D et al (2009) Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms. Arch Neurol 66:102–108

    PubMed  Article  PubMed Central  Google Scholar 

  66. Ito M, Komai K, Mise-Omata S, Iizuka-Koga M, Noguchi Y, Kondo T, Sakai R, Matsuo K, Nakayama T, Yoshie O et al (2019) Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature 565:246–250

    CAS  Article  Google Scholar 

  67. Janda E, Isidoro C, Carresi C, Mollace V (2012) Defective autophagy in Parkinson’s disease: role of oxidative stress. Mol Neurobiol 46:639–661

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. Jenner P (1998) Oxidative mechanisms in nigral cell death in Parkinson’s disease. Mov Disord 13(Suppl 1):24–34

    PubMed  PubMed Central  Google Scholar 

  69. Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53(Suppl 3):S26-36 (discussion S36-28)

    CAS  Article  Google Scholar 

  70. Jin SM, Youle RJ (2012) PINK1- and Parkin-mediated mitophagy at a glance. J Cell Sci 125:795–799

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Jin J, Shie FS, Liu J, Wang Y, Davis J, Schantz AM, Montine KS, Montine TJ, Zhang J (2007) Prostaglandin E2 receptor subtype 2 (EP2) regulates microglial activation and associated neurotoxicity induced by aggregated alpha-synuclein. J Neuroinflammation 4:2

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. Johnson RT, Breedlove SM, Jordan CL (2008) Sex differences and laterality in astrocyte number and complexity in the adult rat medial amygdala. J Comp Neurol 511:599–609

    PubMed  PubMed Central  Article  Google Scholar 

  73. Johnson ME, Stecher B, Labrie V, Brundin L, Brundin P (2019) Triggers, facilitators, and aggravators: redefining Parkinson’s disease pathogenesis. Trends Neurosci 42:4–13

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. Jones R (2010) The roles of PINK1 and Parkin in Parkinson’s disease. PLoS Biol 8:e1000299

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. Kam TI, Hinkle JT, Dawson TM, Dawson VL (2020) Microglia and astrocyte dysfunction in parkinson’s disease. Neurobiol Dis 144:105028

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. Khakh BS, Sofroniew MV (2015) Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18:942–952

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Kim WG, Mohney RP, Wilson B, Jeohn GH, Liu B, Hong JS (2000) Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci 20:6309–6316

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Kim S, Kwon SH, Kam TI, Panicker N, Karuppagounder SS, Lee S, Lee JH, Kim WR, Kook M, Foss CA et al (2019) Transneuronal propagation of pathologic alpha-Synuclein from the gut to the brain models Parkinson’s disease. Neuron 103(627–641):e627

    Article  CAS  Google Scholar 

  79. Kipnis J, Nevo U, Panikashvili D, Alexandrovich A, Yoles E, Akselrod S, Shohami E, Schwartz M (2003) Therapeutic vaccination for closed head injury. J Neurotrauma 20:559–569

    PubMed  Article  PubMed Central  Google Scholar 

  80. Klein C, Westenberger A (2012) Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med 2:a008888

    PubMed  PubMed Central  Article  Google Scholar 

  81. Klingelhoefer L, Reichmann H (2015) Pathogenesis of Parkinson disease–the gut-brain axis and environmental factors. Nat Rev Neurol 11:625–636

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. Komuczki J, Tuzlak S, Friebel E, Hartwig T, Spath S, Rosenstiel P, Waisman A, Opitz L, Oukka M, Schreiner B et al (2019) Fate-mapping of GM-CSF expression identifies a discrete subset of inflammation-driving T helper cells regulated by cytokines IL-23 and IL-1beta. Immunity 50:1289-1304 e1286

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Kumar M, Acevedo-Cintron J, Jhaldiyal A, Wang H, Andrabi SA, Eacker S, Karuppagounder SS, Brahmachari S, Chen R, Kim H et al (2020) Defects in mitochondrial biogenesis drive mitochondrial alterations in PARKIN-deficient human dopamine neurons. Stem Cell Rep 15:629–645

    CAS  Article  Google Scholar 

  85. Kustrimovic N, Rasini E, Legnaro M, Marino F, Cosentino M (2014) Expression of dopaminergic receptors on human CD4 + T lymphocytes: flow cytometric analysis of naive and memory subsets and relevance for the neuroimmunology of neurodegenerative disease. J Neuroimmune Pharmacol 9:302–312

    PubMed  Article  PubMed Central  Google Scholar 

  86. Kustrimovic N, Rasini E, Legnaro M, Bombelli R, Aleksic I, Blandini F, Comi C, Mauri M, Minafra B, Riboldazzi G et al (2016) Dopaminergic receptors on CD4 + T naive and memory lymphocytes correlate with motor impairment in patients with Parkinson’s disease. Sci Rep 6:33738

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Kustrimovic N, Comi C, Magistrelli L, Rasini E, Legnaro M, Bombelli R, Aleksic I, Blandini F, Minafra B, Riboldazzi G et al (2018) Parkinson’s disease patients have a complex phenotypic and functional Th1 bias: cross-sectional studies of CD4 + Th1/Th2/T17 and Treg in drug-naive and drug-treated patients. J Neuroinflammation 15:205

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. LaVoie MJ, Cortese GP, Ostaszewski BL, Schlossmacher MG (2007) The effects of oxidative stress on parkin and other E3 ligases. J Neurochem 103:2354–2368

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. Lecours C, Bordeleau M, Cantin L, Parent M, Paolo TD, Tremblay ME (2018) Microglial implication in Parkinson’s disease: loss of beneficial physiological roles or gain of inflammatory functions? Front Cell Neurosci 12:282

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ et al (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–176

    CAS  PubMed  Article  Google Scholar 

  92. Lenz KM, Nugent BM, Haliyur R, McCarthy MM (2013) Microglia are essential to masculinization of brain and behavior. J Neurosci 33:2761–2772

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Li Q, Barres BA (2018) Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol 18:225–242

    CAS  PubMed  Article  Google Scholar 

  94. Li Q, Cheng Z, Zhou L, Darmanis S, Neff NF, Okamoto J, Gulati G, Bennett ML, Sun LO, Clarke LE et al (2019) Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron 101:207-223 e210

    CAS  PubMed  Article  Google Scholar 

  95. Liddelow SA, Barres BA (2017) Reactive astrocytes: production, function, and therapeutic potential. Immunity 46:957–967

    CAS  Article  Google Scholar 

  96. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Munch AE, Chung WS, Peterson TC et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Lin CCJ, Yu K, Hatcher A, Huang TW, Lee HK, Carlson J, Weston MC, Chen F, Zhang Y, Zhu W, Mohila CA, Ahmed N, Patel AJ, Arenkiel BR, Noebels JL, Creighton CJ, Deneen B (2017) Identification of diverse astrocyte populations and their malignant analogs. Nat Neurosci 20:396–405

  98. Linnerbauer M, Wheeler MA, Quintana FJ (2020) Astrocyte crosstalk in CNS inflammation. Neuron 108:608–622

  99. Liu HF, Ho PW, Leung GC, Lam CS, Pang SY, Li L, Kung MH, Ramsden DB, Ho SL (2017) Combined LRRK2 mutation, aging and chronic low dose oral rotenone as a model of Parkinson’s disease. Sci Rep 7:40887

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Long-Smith CM, Sullivan AM, Nolan YM (2009) The influence of microglia on the pathogenesis of Parkinson’s disease. Prog Neurobiol 89:277–287

    CAS  PubMed  Article  Google Scholar 

  101. Luckheeram RV, Zhou R, Verma AD, Xia B (2012) CD4(+)T cells: differentiation and functions. Clin Dev Immunol 2012:925135

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. Lynch-Day MA, Mao K, Wang K, Zhao M, Klionsky DJ (2012) The role of autophagy in Parkinson’s disease. Cold Spring Harb Perspect Med 2:a009357

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. Maguire-Zeiss KA, Short DW, Federoff HJ (2005) Synuclein, dopamine and oxidative stress: co-conspirators in Parkinson’s disease? Brain Res Mol Brain Res 134:18–23

    CAS  PubMed  Article  Google Scholar 

  104. Mahlknecht P, Seppi K, Poewe W (2015) The concept of prodromal Parkinson’s disease. J Parkinsons Dis 5:681–697

    PubMed  PubMed Central  Article  Google Scholar 

  105. Maiti P, Manna J, Dunbar GL (2017) Current understanding of the molecular mechanisms in Parkinson’s disease: Targets for potential treatments. Transl Neurodegener 6:28

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  106. Marongiu R, Spencer B, Crews L, Adame A, Patrick C, Trejo M, Dallapiccola B, Valente EM, Masliah E (2009) Mutant Pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson’s disease by disturbing calcium flux. J Neurochem 108:1561–1574

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 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 26:41–50

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Martin R, Bajo-Graneras R, Moratalla R, Perea G, Araque A (2015) Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways. Science 349:730–734

    CAS  PubMed  Article  Google Scholar 

  109. Martinez TN, Greenamyre JT (2012) Toxin models of mitochondrial dysfunction in Parkinson’s disease. Antioxid Redox Signal 16:920–934

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. Martinez B, Peplow PV (2017) MicroRNAs in Parkinson’s disease and emerging therapeutic targets. Neural Regen Res 12:1945–1959

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  111. Matsuda W, Furuta T, Nakamura KC, Hioki H, Fujiyama F, Arai R, Kaneko T (2009) Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J Neurosci 29:444–453

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. McGeer PL, Itagaki S, Akiyama H, McGeer EG (1988a) Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 24:574–576

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  113. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988b) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, Fullgrabe J, Jackson A, Sanchez J, Karabiyik M et al (2017) Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 93:1015–1034

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  115. Miller SJ (2018) Astrocyte heterogeneity in the adult central nervous system. Front Cell Neurosci 12:401

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. Miyazaki I, Asanuma M (2009) Approaches to prevent dopamine quinone-induced neurotoxicity. Neurochem Res 34:698–706

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M (1999) Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med 5:49–55

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. Molofsky AV, Kelley KW, Tsai HH, Redmond SA, Chang SM, Madireddy L, Chan JR, Baranzini SE, Ullian EM, Rowitch DH (2014) Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature 509:189–194

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Monsonego A, Zota V, Karni A, Krieger JI, Bar-Or A, Bitan G, Budson AE, Sperling R, Selkoe DJ, Weiner HL (2003) Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest 112:415–422

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Moustafa AA, Chakravarthy S, Phillips JR, Gupta A, Keri S, Polner B, Frank MJ, Jahanshahi M (2016) Motor symptoms in Parkinson’s disease: A unified framework. Neurosci Biobehav Rev 68:727–740

    PubMed  Article  PubMed Central  Google Scholar 

  121. Mouton-Liger F, Jacoupy M, Corvol JC, Corti O (2017) PINK1/Parkin-dependent mitochondrial surveillance: from pleiotropy to Parkinson’s disease. Front Mol Neurosci 10:120

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  122. Nagatsu T, Mogi M, Ichinose H, Togari A (2000) Cytokines in Parkinson’s disease. J Neural Transm Suppl 58:143–151

  123. Narciso L, Parlanti E, Racaniello M, Simonelli V, Cardinale A, Merlo D, Dogliotti E (2016) The response to oxidative DNA damage in neurons: mechanisms and disease. Neural Plast 2016:3619274

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  124. Ng TH, Britton GJ, Hill EV, Verhagen J, Burton BR, Wraith DC (2013) Regulation of adaptive immunity; the role of interleukin-10. Front Immunol 4:129

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Niki E (2008) Lipid peroxidation products as oxidative stress biomarkers. Biofactors 34:171–180

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  127. Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C (2010) Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat 31:763–780

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. Obermeier B, Daneman R, Ransohoff RM (2013) Development, maintenance and disruption of the blood-brain barrier. Nat Med 19:1584–1596

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, Klose J, Shen J (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 279:18614–18622

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  130. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L et al (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–1458

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  131. Picillo M, Nicoletti A, Fetoni V, Garavaglia B, Barone P, Pellecchia MT (2017) The relevance of gender in Parkinson’s disease: a review. J Neurol 264:1583–1607

    PubMed  Article  PubMed Central  Google Scholar 

  132. Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, Squadrito F, Altavilla D, Bitto A (2017) Oxidative Stress: Harms and Benefits for Human Health. Oxid Med Cell Longev 2017:8416763

    PubMed  PubMed Central  Google Scholar 

  133. Podbielska M, Das A, Smith AW, Chauhan A, Ray SK, Inoue J, Azuma M, Nozaki K, Hogan EL, Banik NL (2016) Neuron-microglia interaction induced bi-directional cytotoxicity associated with calpain activation. J Neurochem 139:440–455

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. Reeve AK, Ludtmann MH, Angelova PR, Simcox EM, Horrocks MH, Klenerman D, Gandhi S, Turnbull DM, Abramov AY (2015) Aggregated alpha-synuclein and complex I deficiency: exploration of their relationship in differentiated neurons. Cell Death Dis 6:e1820

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, Chao CC, Patel B, Yan R, Blain M, Alvarez JI, Kébir H, Anandasabapathy N, Izquierdo G, Jung S, Obholzer N, Pochet N, Clish CB, Prinz M, Pra A, Ante lJ, Quintana FJ (2016) Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 22:586–97

  136. Sala G, Marinig D, Arosio A, Ferrarese C (2016) Role of chaperone-mediated autophagy dysfunctions in the pathogenesis of Parkinson’s disease. Front Mol Neurosci 9:157

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  137. Sala Frigerio C, Wolfs L, Fattorelli N, Thrupp N, Voytyuk I, Schmidt I, Mancuso R, Chen WT, Woodbury ME, Srivastava G et al (2019) The major risk factors for Alzheimer’s disease: age, sex, and genes modulate the microglia response to Abeta plaques. Cell Rep 27:1293-1306 e1296

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  138. Samantaray S, Knaryan VH, Guyton MK, Matzelle DD, Ray SK, Banik NL (2007) The parkinsonian neurotoxin rotenone activates calpain and caspase-3 leading to motoneuron degeneration in spinal cord of Lewis rats. Neuroscience 146:741–755

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 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 52:1054–1066

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. Sariola H, Saarma M (2003) Novel functions and signalling pathways for GDNF. J Cell Sci 116:3855–3862

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  141. Sato K (2015) Effects of microglia on neurogenesis. Glia 63:1394–1405

    PubMed  PubMed Central  Article  Google Scholar 

  142. Schapira AH, Holt IJ, Sweeney M, Harding AE, Jenner P, Marsden CD (1990) Mitochondrial DNA analysis in Parkinson’s disease. Mov Disord 5:294–297

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  143. Schapira AH, Mann VM, Cooper JM, Dexter D, Daniel SE, Jenner P, Clark JB, Marsden CD (1990b) Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson’s disease. J Neurochem 55:2142–2145

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  144. Scudamore O, Ciossek T (2018) Increased oxidative stress exacerbates alpha-synuclein aggregation in vivo. J Neuropathol Exp Neurol 77:443–453

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  145. Selvaraj S, Piramanayagam S (2019) Impact of gene mutation in the development of Parkinson’s disease. Genes Dis 6:120–128

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. Shields DC, Haque A, Banik NL (2020) Neuroinflammatory responses of microglia in central nervous system trauma. J Cereb Blood Flow Metab 40:S25–S33

    PubMed  Article  PubMed Central  Google Scholar 

  147. Siddiqui A, Hanson I, Andersen JK (2012) Mao-B elevation decreases parkin’s ability to efficiently clear damaged mitochondria: protective effects of rapamycin. Free Radic Res 46:1011–1018

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. Sierra A, Gottfried-Blackmore A, Milner TA, McEwen BS, Bulloch K (2008) Steroid hormone receptor expression and function in microglia. Glia 56:659–674

    PubMed  Article  PubMed Central  Google Scholar 

  149. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R et al (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841

    CAS  Article  Google Scholar 

  150. Socodato R, Portugal CC, Canedo T, Rodrigues A, Almeida TO, Henriques JF, Vaz SH, Magalhaes J, Silva CM, Baptista FI et al (2020) Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration. Cell Rep 31:107796

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  151. Solano RM, Casarejos MJ, Menendez-Cuervo J, Rodriguez-Navarro JA, Garcia de Yebenes J, Mena MA (2008) Glial dysfunction in parkin null mice: effects of aging. J Neurosci 28:598–611

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci 29:13578–13588

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. Sulzer D (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci 30:244–250

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  155. Tanji K, Odagiri S, Maruyama A, Mori F, Kakita A, Takahashi H, Wakabayashi K (2013) Alteration of autophagosomal proteins in the brain of multiple system atrophy. Neurobiol Dis 49:190–198

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  156. Tay TL, Savage JC, Hui CW, Bisht K, Tremblay ME (2017) Microglia across the lifespan: from origin to function in brain development, plasticity and cognition. J Physiol 595:1929–1945

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  157. Teismann P, Schulz JB (2004) Cellular pathology of Parkinson’s disease: astrocytes, microglia and inflammation. Cell Tissue Res 318:149–161

    PubMed  Article  PubMed Central  Google Scholar 

  158. Testa CM, Sherer TB, Greenamyre JT (2005) Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures. Brain Res Mol Brain Res 134:109–118

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  159. Thakkar R, Wang R, Wang J, Vadlamudi RK, Brann DW (2018) 17beta-Estradiol Regulates Microglia Activation and Polarization in the Hippocampus Following Global Cerebral Ischemia. Oxid Med Cell Longev 2018:4248526

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  160. Villa A, Gelosa P, Castiglioni L, Cimino M, Rizzi N, Pepe G, Lolli F, Marcello E, Sironi L, Vegeto E et al (2018) Sex-specific features of microglia from adult mice. Cell Rep 23:3501–3511

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. Wang S, Chu CH, Stewart T, Ginghina C, Wang Y, Nie H, Guo M, Wilson B, Hong JS, Zhang J (2015) alpha-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation. Proc Natl Acad Sci U S A 112:E1926-1935

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. Weinhard L, di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U, Exiga M, Vadisiute A, Raggioli A, Schertel A et al (2018) Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun 9:1228

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  163. Wheeler MA, Quintana FJ (2019) Regulation of astrocyte functions in multiple sclerosis. Cold Spring Harb Perspect Med 9:a029009

  164. Wheeler MA, Clark IC, Tjon EC, Li Z, Zandee SEJ, Couturier CP, Watson BR, Scalisi G, Alkwai S, Rothhammer V, Rotem A, Heyman JA, Thaploo S, Sanmarco LM, Ragoussis J, Weitz DA, Petrecca K, Moffitt JR, Becher B, Antel JP, Prat A, Quintana FJ (2020) MAFGdriven astrocytes promote CNS inflammation. Nature 578:593–599

  165. Wong D, Dorovini-Zis K, Vincent SR (2004) Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood-brain barrier. Exp Neurol 190:446–455

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  166. Wu SY, Chen YW, Tsai SF, Wu SN, Shih YH, Jiang-Shieh YF, Yang TT, Kuo YM (2016) Estrogen ameliorates microglial activation by inhibiting the Kir2.1 inward-rectifier K(+) channel. Sci Rep 6:22864

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. Yang QQ, Zhou JW (2019) Neuroinflammation in the central nervous system: Symphony of glial cells. Glia 67:1017–1035

    PubMed  Article  PubMed Central  Google Scholar 

  168. Yasuda T, Mochizuki H (2010) Use of growth factors for the treatment of Parkinson’s disease. Expert Rev Neurother 10:915–924

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  169. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W, Zhou Y, Hong JS et al (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19:533–542

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported in part by funding from Veterans Administration (1I01BX002349-01, 2I01 BX001262-05, 1I01 BX004269-01), NIH-NINDS (R01 NS62327 and 1R21NS118393-01), and the South Carolina State Spinal Cord Research Fund (SCIRF-2015P-01, SCIRF-2015P-04, SCIRF-2015-I-01, SCIRF-2016 I-03, and SCIRF #2018 I-01).

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Vandana Zaman conceived, designed, wrote the manuscript, and drew the figures. Donald Shields, Ramsha Shams, Kelsey Drasites, and Denise Matzelle edited the manuscript. Azizul Haque and Naren Banik conceived, designed, and edited the manuscript. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Azizul Haque or Narendra L. Banik.

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Zaman, V., Shields, D.C., Shams, R. et al. Cellular and molecular pathophysiology in the progression of Parkinson’s disease. Metab Brain Dis (2021). https://doi.org/10.1007/s11011-021-00689-5

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Keywords

  • Autophagy
  • Neuroinflammation
  • Neuron
  • Oxidative damage
  • Parkinson’s disease
  • Substantia nigra