Multiple lines of evidence indicate that immune system dysfunction has a role in Parkinson disease (PD); this evidence includes clinical and genetic associations between autoimmune disease and PD, impaired cellular and humoral immune responses in PD, imaging evidence of inflammatory cell activation and evidence of immune dysregulation in experimental models of PD. However, the mechanisms that link the immune system with PD remain unclear, and the temporal relationships of innate and adaptive immune responses with neurodegeneration are unknown. Despite these challenges, our current knowledge provides opportunities to develop immune-targeted therapeutic strategies for testing in PD, and clinical studies of some approaches are under way. In this Review, we provide an overview of the clinical observations, preclinical experiments and clinical studies that provide evidence for involvement of the immune system in PD and that help to define the nature of this association. We consider autoimmune mechanisms, central and peripheral inflammatory mechanisms and immunogenetic factors. We also discuss the use of this knowledge to develop immune-based therapeutic approaches, including immunotherapy that targets α-synuclein and the targeting of immune mediators such as inflammasomes. We also consider future research and clinical trials necessary to maximize the potential of targeting the immune system.
The relationship between neuroinflammation and Parkinson disease (PD) is unclear because the exact mechanisms involved remain to be elucidated.
Clinical and laboratory findings have linked autoimmune diseases, impaired cellular and humoral immune responses, inflammatory cell activation and immune dysregulation with PD pathogenesis.
Establishing the temporal relationships of innate and adaptive immune responses with the initiation and progression of neurodegeneration will provide insights into the underlying pathophysiology.
Most clinical studies of immune-targeted therapies in PD have been limited by cross-sectional methodology and relatively small sample sizes.
Clinical trials of therapies that target α-synuclein and other immune targets have been conducted, but the safety and efficacy of such immunotherapies in PD remain to be established.
Longitudinal studies are needed to identify groups of patients with PD who are most suitable for immunotherapy and to determine the long-term efficacy, outcome and viability of such treatments.
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Obeso, J. A., Stamelou, M., Goetz, C. G., Poewe, W. & Lang, A. E. Past, present, and future of Parkinson’s disease: a special essay on the 200th anniversary of the shaking palsy. Mov. Disord. 32, 1264–1310 (2017). This review provides a history of and insights into the clinical features and pathogenesis of PD.
GBD 2016 Parkinson’s Disease Collaborators. Global, regional, and national burden of Parkinson’s disease, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol. 17, 939–953 (2018).
Kalia, L. V. & Lang, A. E. Parkinson’s disease. Lancet 386, 896–912 (2015).
Johnson, M. E., Stecher, B., Labrie, V., Brundin, L. & Brundin, P. Triggers, facilitators, and aggravators: redefining Parkinson’s disease pathogenesis. Trends Neurosci. 42, 4–13 (2019).
Chao, Y., Wong, S. C. & Tan, E. K. Evidence of inflammatory system involvement in Parkinson’s disease. Biomed. Res. Int. 2014, 308654 (2014).
Moehle, M. S. & West, A. B. M1 and M2 immune activation in Parkinson’s disease: foe and ally? Neuroscience 302, 59–73 (2015).
Jankovic, J. Pathogenesis-targeted therapeutic strategies in Parkinson’s disease. Mov. Disord. 34, 41–44 (2019).
Rugbjerg, K., Friis, S., Ritz, B., Schernhammer, E. S. & Korbo, L. Autoimmune disease and risk for Parkinson disease: a population-based case-control study. Neurology 73, 1462–1468 (2009). This is a population study on the association between autoimmune diseases and the risk of PD.
Li, X., Sundquist, J. & Sundquist, K. Subsequent risks of Parkinson disease in patients with autoimmune and related disorders: a nationwide epidemiological study from Sweden. Neurodegener. Dis. 10, 277–284 (2012).
Sheu, J. J., Wang, K. H., Lin, H. C. & Huang, C. C. Psoriasis is associated with an increased risk of parkinsonism: a population-based 5-year follow-up study. J. Am. Acad. Dermatol. 68, 992–999 (2013).
Chung, J., Takeshita, J., Shin, D. B., Haynes, K. & Arnold, S. E. The risk of Parkinson’s disease in patients with psoriasis: a population-based cohort study. J. Invest. Dermatol. 135, 53–55 (2015).
Wu, M. C., Xu, X., Chen, S. M., Tyan, Y. S. & Chiou, J. Y. Impact of Sjogren’s syndrome on Parkinson’s disease: a nationwide case-control study. PLoS One 12, e0175836 (2017).
Amanat, M., Salehi, M. & Rezaei, N. Neurological and psychiatric disorders in psoriasis. Rev. Neurosci. 29, 805–813 (2018).
Chang, C. C., Lin, T. M., Chang, Y. S., Chen, W. S. & Sheu, J. J. Autoimmune rheumatic diseases and the risk of Parkinson disease: a nationwide population-based cohort study in Taiwan. Ann. Med. 50, 83–90 (2018).
Ju, U. H. et al. Risk of Parkinson disease in Sjogren syndrome administered ineffective immunosuppressant therapies: a nationwide population-based study. Medicine 98, e14984 (2019).
Liu, F. C. et al. Inverse association of Parkinson disease with systemic Lupus Erythematosus: a nationwide population-based study. Medicine 94, e2097 (2015).
Baizabal-Carvallo, J. F. & Jankovic, J. Stiff-person syndrome: insights into a complex autoimmune disorder. J. Neurol. Neurosurg. Psychiatry 86, 840–848 (2015).
Baizabal-Carvallo, J. F. & Jankovic, J. Autoimmune and paraneoplastic movement disorders: an update. J. Neurol. Sci. 385, 175–184 (2018).
Raj, T., Rothamel, K., Mostafavi, S., Ye, C. & Lee, M. N. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science 344, 519–523 (2014). This study shows overlap between autoimmune and neurodegenerative diseases in the overexpression of some risk alleles.
Rivas, M. A., Avila, B. E., Koskela, J., Huang, H. & Stevens, C. Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population. PLoS Genet. 14, e1007329 (2018).
Holmans, P., Moskvina, V., Jones, L., Sharma, M. & Vedernikov, A. A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson’s disease. Hum. Mol. Genet. 22, 1039–1049 (2013).
Lai, S. et al. Herpes zoster correlates with increased risk of Parkinson’s disease in older people. Medicine 96, 6075 (2017).
Limphaibool, N., Iwanowski, P., Holstad, M. J. V., Kobylarek, D. & Kozubski, W. Infectious etiologies of Parkinsonism: pathomechanisms and clinical implications. Front. Neurol. 10, 652 (2019).
Akhtar, R. S., Licata, J. P., Luk, K. C., Shaw, L. M. & Trojanowski, J. Q. Measurements of auto-antibodies to α-synuclein in the serum and cerebral spinal fluids of patients with Parkinson’s disease. J. Neurochem. 145, 489–503 (2018).
Bach, J. P. & Falkenburger, B. H. What autoantibodies tell us about the pathogenesis of Parkinson’s disease: an editorial for ‘Measurements of auto-antibodies to α-synuclein in the serum and cerebral spinal fluids of patients with Parkinson’s disease’ on page 489. J. Neurochem. 145, 433–435 (2018).
Yanamandra, K., Gruden, M. A., Casaite, V., Meskys, R. & Forsgren, L. Alpha-synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson’s disease patients. PLoS One 6, e18513 (2011).
Gruden, M. A., Sewell, R. D., Yanamandra, K., Davidova, T. V. & Kucheryanu, V. G. Immunoprotection against toxic biomarkers is retained during Parkinson’s disease progression. J. Neuroimmunol. 233, 221–227 (2011).
Gruden, M. A., Yanamandra, K., Kucheryanu, V. G., Bocharova, O. R. & Sherstnev, V. V. Correlation between protective immunity to α-synuclein aggregates, oxidative stress and inflammation. Neuroimmunomodulation 19, 334–342 (2012).
Besong-Agbo, D., Wolf, E., Jessen, F., Oechsner, M. & Hametner, E. Naturally occurring alpha-synuclein autoantibody levels are lower in patients with Parkinson disease. Neurology 80, 169–175 (2013).
Brudek, T., Winge, K., Folke, J., Christensen, S. & Fog, K. Autoimmune antibody decline in Parkinson’s disease and multiple system atrophy; a step towards immunotherapeutic strategies. Mol. Neurodegener. 12, 44 (2017).
Horvath, I., Iashchishyn, I. A., Forsgren, L. & Morozova-Roche, L. A. Immunochemical detection of alpha-synuclein autoantibodies in Parkinson’s disease: correlation between plasma and cerebrospinal fluid levels. ACS Chem. Neurosci. 8, 1170–1176 (2017).
Scott, K. M., Kouli, A., Yeoh, S. L., Clatworthy, M. R. & Williams-Gray, C. H. A systemic review and meta-analysis of alpha synuclein auto-antibodies in Parkinson’s disease. Front. Neurol. 1, 815 (2018). This is a review of the mechanistic basis of the development and function of autoantibodies to α-synuclein in PD.
Papachroni, K. K., Ninkina, N., Papapanagiotou, A., Hadjigeorgiou, G. M. & Xiromerisiou, G. Autoantibodies to alpha-synuclein in inherited Parkinson’s disease. J. Neurochem. 101, 749–756 (2007).
Akhtar, R. S., Licata, J. P., Luk, K. C., Shaw, L. M. & Trojanowski, J. Q. Measurements of auto-antibodies to alpha-synuclein in the serum and cerebral spinal fluids of patients with Parkinson’s disease. J. Neurochem. 145, 489–503 (2018).
Sulzer, D., Alcalay, R. N., Garretti, F., Cote, L. & Kanter, E. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature 546, 656–661 (2017).
Louveau, A. et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphaticvasculature. Nat. Neurosci. 21, 1380–1391 (2018).
Brioschi, S. & Colonna, M. The CNS immune-privilege goes down the drain(age). Trends Pharmacol. Sci. 40, 1–3 (2019).
Turkheimer, F. E. et al. The methodology of TSPO imaging with positron emission tomography. Biochem. Soc. Trans. 43, 586–592 (2015).
Roussakis, A. A. & Piccini, P. Molecular imaging of neuroinflammation in idiopathic Parkinson’s disease. Int. Rev. Neurobiol. 141, 347–363 (2018). This is a review of PET studies with tracers specific for microglia and the development of astrocyte-specific PET tracers.
Gerhard, A., Pavese, N., Hotton, G., Turkheimer, F. & Es, M. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol. Dis. 21, 404–412 (2006).
Hirsch, E. C. & Hunot, S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 8, 382–397 (2009).
Terada, T., Yokokura, M., Yoshikawa, E., Futatsubashi, M. & Kono, S. Extrastriatal spreading of microglial activation in Parkinson’s disease: a positron emission tomography study. Ann. Nucl. Med. 30, 579–587 (2016).
Varnäs, K., Cselényi, Z., Jucaite, A., Halldin, C. & Svenningsson. PET imaging of [11C]PBR28 in Parkinson’s disease patients does not indicate increased binding to TSPO despite reduced dopamine transporter binding. Eur. J. Nucl. Med. Mol. Imaging 46, 367–375 (2019).
Horti, A. G., Naik, R., Foss, C. A., Minn, I. & Misheneva, V. PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R). Proc. Natl Acad. Sci. USA 116, 1686–1691 (2019).
Van Weehaeghe, D., Koole, M., Schmidt, M. E., Deman, S. & Jacobs, A. H. [11C]JNJ54173717, a novel P2X7 receptor radioligand as marker for neuroinflammation: human biodistribution, dosimetry, brain kinetic modelling and quantification of brain P2X7 receptors in patients with Parkinson’s disease and healthy volunteers. Eur. J. Nucl. Med. Mol. Imaging 46, 1–14 (2019).
Misra, A., Chakrabarti, S. S. & Gambhir, I. S. New genetic players in late-onset Alzheimer’s disease: findings of genome-wide association studies. Indian. J. Med. Res. 148, 135–144 (2018).
Pluvinage, J. V. et al. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 568, 187–192 (2019).
Streit, W. J., Braak, H., Xue, Q. S. & Bechmann, I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol. 118, 475–485 (2009).
Bae, E. J., Lee, H. J., Rockenstein, E., Ho, D. H. & Park, E. B. Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J. Neurosci. 32, 13454–13469 (2012).
Duffy, M. F., Collier, T. J., Patterson, J. R., Kemp, C. J. & Luk, K. C. Correction to: Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration. J. Neuroinflammation 15, 169 (2018).
Doorn, K. J., Moors, T., Drukarch, B., Van de Berg., W. D. J. & Lucassen, P. J. Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy disease cases and Parkinson’s disease patients. Acta Neuropathol. Commun. 7, 90 (2014).
Fellner, L., Irschick, R. & Schanda, K. Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360 (2013).
Harms, A. S., Delic, V., Thome, A. D., Bryant, N. & Liu, Z. α-Synuclein fibrils recruit peripheral immune cells in the rat brain prior to neurodegeneration. Acta Neuropathol. Commun. 5, 85 (2017).
Guo, H., Callaway, J. B. & Ting, J. P. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687 (2015). This is a review of the role of inflammasomes and potential therapeutics to target inflammasome activity in medical conditions.
Panicker, N., Sarkar, S., Harischandra, D. S., Neal, M. & Kam, T. I. Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia. J. Exp. Med. 216, 1411–1430 (2019).
Yun, S. P., Kam, T. I., Panicker, N., Kim, S. & Oh, Y. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat. Med. 24, 931–938 (2018).
Hinkle, J. T., Dawson, V. L. & Dawson, T. M. The A1 astrocyte paradigm: new avenues for pharmacological intervention in neurodegeneration. Mov. Disord. 34, 959–969 (2019).
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C. & Bohlen, C. J. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).
Harms, A. S., Cao, S., Rowse, A. L., Thome, A. D. & Li, X. MHCII is required for alpha-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J. Neurosci. 33, 9592–9600 (2013).
Waisman, A. & Johann, L. Antigen-presenting cell diversity for T cell reactivation in central nervous system autoimmunity. J. Mol. Med. 96, 1279–1292 (2018).
Williams, G. P., Schonhoff, A. M., Jurkuvenaite, A., Thome, A. D. & Standaert, D. G. Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson’s disease. J. Neuroinflammation 15, 244 (2018).
Duffy, M. F., Collier, T. J. & Patterson, J. R. Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration. J. Neuroinflammation 15, 129 (2018).
Lin, C. H., Chen, C. C., Chiang, H. L., Liou, J. M. & Chang, C. M. Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson’s disease. J. Neuroinflammation 16, 129 (2019).
Mogi, M., Harada, M., Narabayashi, H., Inagaki, H. & Minami, M. Interleukin (IL)-1β, IL-2, IL-4, IL-6 and transforming growth factor-α levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neurosci. Lett. 211, 13–16 (1996).
Brodacki, B., Staszewski, J., Toczylowska, B., Kozlowska, E. & Drela, N. Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFα, and INFγ concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci. Lett. 441, 158–162 (2008).
Bauernfeind, F. G. et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791 (2009).
Lee, P. P. et al. Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells. Nat. Commun. 8, 1576 (2017).
Wang, W. et al. Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein. Proc. Natl Acad. Sci. USA 113, 9587–9592 (2016).
Codolo, G., Plotegher, N., Pozzobon, T., Brucale, M. & Tessari, I. Triggering of inflammasome by aggregated alpha-synuclein, an inflammatory response in synucleinopathies. PLoS One 8, e55375 (2013).
Gordon, R., Albornoz, E. A., Christie, D. C., Langley, M. R. & Kumar, V. Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice. Sci. Transl. Med. 10, 465 (2018). This is a proof-of-concept study showing that the inflammasome inhibitor MCC950 abolished fibrillar α-synuclein-mediated inflammasome activation in mouse microglial cells.
Lee, S. J. Origins and effects of extracellular alpha-synuclein: implications in Parkinson’s disease. J. Mol. Neurosci. 34, 17–22 (2008).
Wang, W. et al. Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein alpha-synuclein. Proc. Natl Acad. Sci. USA 113, 9587–9592 (2016).
Bylicky, M. A., Mueller, G. P. & Day, R. M. Mechanisms of endogenous neuroprotective effects of astrocytes in brain injury. Oxid. Med. Cell. Longev. https://doi.org/10.1155/2018/6501031 (2018).
Shao, W. et al. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via alphaB-crystallin. Nature 494, 90–94 (2013).
Kempuraj, D., Selvakumar, G. P., Zaheer, S., Thangavel, R. & Ahmed, M. E. Cross-talk between glia, neurons and mast cells in neuroinflammation associated with Parkinson’s disease. J. Neuroimmune Pharmacol. 13, 100–112 (2018).
Jones, M. K., Nair, A. & Gupta, M. Mast cells in neurodegenerative disease. Front. Cell. Neurosci. 13, 171 (2019).
Wijeyekoon, R. S., Kronenberg-Versteeg, D., Scott, K. M., Hayat, S. & Jones, J. L. Monocyte function in Parkinson’s disease and the impact of autologous serum on phagocytosis. Front. Neurol. 9, 870 (2018).
Harms, A. S., Thome, A. D., Yan, Z., Schonhoff, A. M. & Williams, G. P. Peripheral monocyte entry is required for alpha-synuclein induced inflammation and neurodegeneration in a model of Parkinson disease. Exp. Neurol. 300, 179–187 (2019).
Cook, D. A., Kannarkat, G. T., Cintron, A. F., Butkovich, L. M. & Fraser, K. B. LRRK2 levels in immune cells are increased in Parkinson’s disease. NPJ Parkinsons Dis. 3, 11 (2017).
Stefanis, L. et al. How is alpha-synuclein cleared from the cell? J. Neurochem. 150, 577–590 (2019).
Alcalay, R. N., Levy, O. A., Waters, C. C., Fahn, S. & Ford, B. Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain 138, 2648–2658 (2015).
Atashrazm, F., Hammond, D., Perera, G., Dobson-Stone, C. & Mueller, N. Reduced glucocerebrosidase activity in monocytes from patients with Parkinson’s disease. Sci. Rep. 8, 15446 (2018).
Witoelar, A., Jansen, I. E., Wang, Y., Desikan, R. S. & Gibbs, J. R. Genome-wide pleiotropy between Parkinson disease and autoimmune diseases. JAMA Neurol. 74, 780–792 (2017).
Ahmed, I., Tamouza, R., Delord, M., Krishnamoorthy, R. & Tzourio, C. Association between Parkinson’s disease and the HLA-DRB1 locus. Mov. Disord. 27, 1104–1110 (2012).
Kustrimovic, N. et al. 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 (2018).
Sommer, A., Marxreiter, F., Krach, F., Fadler, T. & Grosch, J. Th17 lymphocytes induce neuronal cell death in a human iPSC-based model of Parkinson’s disease. Cell Stem Cell 24, 1006 (2019).
Bas, J., Calopa, M., Mestre, M., Mollevi, D. G. & Cutillas, B. Lymphocyte populations in Parkinson’s disease and in rat models of parkinsonism. J. Neuroimmunol. 113, 145–152 (2001).
Saunders, J. A., Estes, K. A., Kosloski, L. M., Allen, H. E. & Dempsey, K. M. CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J. Neuroimmune Pharmacol. 7, 927–938 (2012).
McGeer, P. L., Itagaki, S. & McGeer, E. G. Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol. 76, 550–557 (1988).
Fiszer, U., Mix, E., Fredrikson, S., Kostulas, V. & Link, H. Parkinson’s disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood. Acta Neurol. Scand. 90, 160–166 (1994).
Schroder, J. B., Pawlowski, M., Meyer Zu Horste, G., Gross, C. C. & Wiendl, H. Immune cell activation in the cerebrospinal fluid of patients with Parkinson’s disease. Front. Neurol. 9, 1081 (2018).
Kortekaas, R., Leenders, K. L., van Oostrom, J. C., Vaalburg, W. & Bart, J. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann. Neurol. 57, 176–179 (2005).
Ham, J. H., Yi, H., Sunwoo, M. K., Hong, J. Y. & Sohn, Y. H. Cerebral microbleeds in patients with Parkinson’s disease. J. Neurol. 261, 1628–1635 (2014).
Janelidze, S., Lindqvist, D., Francardo, V., Hall, S. & Zetterberg, H. Increased CSF biomarkers of angiogenesis in Parkinson disease. Neurology 85, 1834–1842 (2015).
Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D. & Rouhani, S. J. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).
Brochard, V., Combadiere, B., Prigent, A., Laouar, Y. & Perrin, A. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest. 119, 182–192 (2009).
Liu, Z., Huang, Y., Cao, B. B., Qiu, Y. H. & Peng, Y. P. Th17 cells induce dopaminergic neuronal death via LFA-1/ICAM-1 interaction in a mouse model of Parkinson’s disease. Mol. Neurobiol. 54, 7762–7776 (2017).
Cebrián, C. et al. MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat. Commun. 5, 3633 (2014).
Mogi, M. et al. Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci. Lett. 165, 208–210 (1994).
Mogi, M., Harada, M., Narabayashi, H., Inagaki, H. & Minami, M. Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neurosci. Lett. 221, 13–16 (1996).
Nagatsu, T., Mogi, M., Ichinose, H. & Togari, A. Cytokines in Parkinson’s disease. J. Neural. Transm. Suppl. 58, 143–151 (2000).
Karpenko, M. N., Vasilishina, A. A., Gromova, E. A., Muruzheva, Z. M. & Bernadotte, A. Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-6, interleukin-10, and tumor necrosis factor-alpha levels in CSF and serum in relation to the clinical diversity of Parkinson’s disease. Cell. Immunol. 327, 77–82 (2018).
Brodacki, B., Staszewski, J., Toczylowska, B., Kozlowska, E. & Drela, N. Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci. Lett. 441, 158–162 (2008).
Reale, M. et al. Peripheral cytokines profile in Parkinson’s disease. Brain Behav. Immun. 23, 55–63 (2009).
Chen, H., O’Reilly, E. J., Schwarzschild, M. A. & Ascherio, A. Peripheral inflammatory biomarkers and risk of Parkinson’s disease. Am. J. Epidemiol. 167, 90–95 (2008).
Lian, T. H., Guo, P., Zuo, L. J., Hu, Y. & Yu, S. Y. Tremor-dominant in Parkinson disease: the relevance to iron metabolism and inflammation. Front. Neurosci. 13, 255 (2019).
Dufek, M., Rektorova, I., Thon, V., Lokaj, J. & Rektor, I. Interleukin-6 may contribute to mortality in Parkinsons disease patients: a 4-year prospective study. Parkinsons Dis. 2015, 898192 (2015).
Sathe, K., Maetzler, W., Lang, J. D., Mounsey, R. B. & Fleckenstein, C. S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-alpha pathway. Brain 135, 3336–3347 (2012).
Rydbirk, R., Elfving, B., Andersen, M. D., Langbol, M. A. & Folke, J. Cytokine profiling in the prefrontal cortex of Parkinson’s disease and multiple system atrophy patients. Neurobiol. Dis. 106, 269–278 (2017).
Cardona, A. E., Li, M., Liu, L., Savarin, C. & Ransohoff, R. M. Chemokines in and out of the central nervous system: much more than chemotaxis and inflammation. J. Leukoc. Biol. 84, 587–594 (2008).
Shimoji, M., Pagan, F., Healton, E. B. & Mocchetti, I. CXCR4 and CXCL12 expression is increased in the nigro-striatal system of Parkinson’s disease. Neurotox. Res. 16, 318–328 (2009).
Bagheri, V., Khorramdelazad, H., Hassanshahi, G., Moghadam-Ahmadi, A. & Vakilian, A. CXCL12 and CXCR4 in the peripheral blood of patients with Parkinson’s disease. Neuroimmunomodulation 25, 201–205 (2018).
Ross, O. A., O’Neill, C., Rea, I. M., Lynch, T. & Gosal, D. Functional promoter region polymorphism of the proinflammatory chemokine IL-8 gene associates with Parkinson’s disease in the Irish. Hum. Immunol. 65, 340–346 (2004).
Qiu, X., Xiao, Y., Wu, J., Gan, L. & Huang, Y. C-reactive protein and risk of Parkinson’s disease: a systematic review and meta-analysis. Front. Neurol. 10, 384 (2019). This is a meta-analysis of data on the association between CRP and risk of PD.
Lindqvist, D., Hall, S., Surova, Y., Nielsen, H. M. & Janelidze, S. Cerebrospinal fluid inflammatory markers in Parkinson’s disease-associations with depression, fatigue, and cognitive impairment. Brain Behav. Immun. 33, 183–189 (2013).
Hall, S., Janelidze, S., Surova, Y., Widner, H. & Zetterberg, H. Cerebrospinal fluid concentrations of inflammatory markers in Parkinson’s disease and atypical parkinsonian disorders. Sci. Rep. 8, 13276 (2018).
Sanjari Moghaddam, H., Valitabar, Z., Ashraf-Ganjouei, A., Mojtahed Zadeh, M. & Ghazi Sherbaf, F. Cerebrospinal fluid C-reactive protein in Parkinson’s disease: associations with motor and non-motor symptoms. Neuromolecular Med. 20, 376–385 (2018).
Yamada, T., McGeer, P. L. & McGeer, E. G. Lewy bodies in Parkinson’s disease are recognized by antibodies to complement proteins. Acta Neuropathol. 84, 100–104 (1992).
Double, K. L., Rowe, D. B., Carew-Jones, F. M., Hayes, M. & Chan, D. K. Anti-melanin antibodies are increased in sera in Parkinson’s disease. Exp. Neurol. 217, 297–301 (2009).
Gelders, G., Baekelandt, V. & Van der Perren, A. Linking neuroinflammation and neurodegeneration in Parkinson’s disease. J. Immunol. Res. 2018, 4784628 (2018).
Klingelhoefer, L. & Reichmann, H. Pathogenesis of Parkinson disease–the gut-brain axis and environmental factors. Nat. Rev. Neurol. 11, 625–636 (2015).
Chapelet, G., Leclair-Visonneau, L., Clairembault, T., Neunlist, M. & Derkinderen, P. Can the gut be the missing piece in uncovering PD pathogenesis? Parkinsonism Relat. Disord. 59, 26–31 (2019).
Braak, H., Rüb, U., Gai, W. P. & Del Tredici, K. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural. Transm. 110, 517–536 (2003).
Hawkes, C. H., Del Tredici, K. & Braak, H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol. Appl. Neurobiol. 33, 599–614 (2007).
Kim, S., Kwon, S. H., Kam, T. I., Panicker, N. & Karuppagounder, S. S. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron 103, 1–15 (2019).
Svensson, E., Horvath-Puho, E., Thomsen, R. W., Djurhuus, J. C. & Pedersen, L. Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 78, 522–529 (2015).
Parashar, A. & Udayabanu, M. Gut microbiota: implications in Parkinson’s disease. Parkinsonism Relat. Disord. 38, 1–7 (2017).
Rietdijk, C. D., Perez-Pardo, P., Garssen, J., van Wezel, R. J. & Kraneveld, A. D. Exploring Braak’s hypothesis of Parkinson’s disease. Front. Neurol. 8, 37 (2017).
Su, A., Gandhy, R., Barlow, C. & Triadafilopoulos, G. A practical review of gastrointestinal manifestations in Parkinson’s disease. Parkinsonism Relat. Disord. 39, 17–26 (2017).
Devos, D., Lebouvier, T., Lardeux, B., Biraud, M. & Rouaud, T. Colonic inflammation in Parkinson’s disease. Neurobiol. Dis. 50, 42–48 (2013).
Lin, J. C., Lin, C. S., Hsu, C. W., Lin, C. L. & Kao, C. H. Association between Parkinson’s disease and inflammatory bowel disease: a nationwide Taiwanese retrospective cohort study. Inflamm. Bowel Dis. 22, 1049–1055 (2016).
Peter, I., Dubinsky, M., Bressman, S., Park, A. & Lu, C. Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol. 75, 939–946 (2018).
Nerius, M., Doblhammer, G. & Tamguney, G. GI infections are associated with an increased risk of Parkinson’s disease. Gut https://doi.org/10.1136/gutjnl-2019-318822 (2019).
Dardiotis, E., Tsouris, Z., Mentis, A. A., Siokas, V. & Michalopoulou, A. H. pylori and Parkinson’s disease: meta-analyses including clinical severity. Clin. Neurol. Neurosurg. 175, 16–24 (2018).
McGee, D. J., Lu, X. H. & Disbrow, E. A. Stomaching the possibility of a pathogenic role for Helicobacter pylori in Parkinson’s disease. J. Parkinsons Dis. 8, 367–374 (2018).
Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S. & Shastri, G. G. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480 (2016). This study shows that colonization of mice that overexpress α-synuclein with microorganisms from patients with PD affected motor function.
Choi, J. G., Kim, N., Ju, I. G., Eo, H. & Lim, S. M. Oral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice. Sci. Rep. 8, 1275 (2018).
Perez-Pardo, P., Dodiya, H. B., Engen, P. A., Forsyth, C. B. & Huschens, A. M. Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice. Gut 68, 829–843 (2019).
Barichella, M., Pacchetti, C., Bolliri, C., Cassani, E. & Iorio, L. Probiotics and prebiotic fiber for constipation associated with Parkinson disease: an RCT. Neurology 87, 1274–1280 (2016).
Magistrelli, L., Amoruso, A., Mogna, L., Graziano, T. & Cantello, R. Probiotics may have beneficial effects in Parkinson’s disease: in vitro evidence. Front. Immunol. 10, 969 (2019).
Buhat, D. M. & Tan, E. K. Genetic testing of LRRK2 in Parkinson’s disease: is there a clinical role? Parkinsonism Relat. Disord. 20, 54–56 (2014).
Foo, J. N., Chung, S. J., Tan, L. C., Liany, H. & Ryu, H. S. Linking a genome-wide association study signal to a LRRK2 coding variant in Parkinson’s disease. Mov. Disord. 31, 484–487 (2016).
Hui, K. Y., Fernandez-Hernandez, H., Hu, J., Schaffner, A. & Pankratz, N. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci. Transl. Med. 10, eaai7795 (2018).
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E. & Dehejia, A. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047 (1997).
Tan, E. K. & Skipper, L. M. Pathogenic mutations in Parkinson disease. Hum. Mutat. 28, 641–653 (2007).
Deng, H., Wang, P. & Jankovic, J. The genetics of Parkinson disease. Ageing Res. Rev. 42, 72–85 (2018).
Prigent, A., Lionnet, A., Durieu, E., Chapelet, G. & Bourreille, A. Enteric alpha-synuclein expression is increased in Crohn’s disease. Acta Neuropathol. 137, 359–361 (2019).
Liu, Z. et al. LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network. Hum. Mol. Genet. 27, 385–395 (2018).
Mir, R., Tonelli, F., Lis, P., Macartney, T. & Polinski, N. K. The Parkinson’s disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. Biochemical J. 475, 1861–1883 (2018).
Purlyte, E., Dhekne, H. S., Sarhan, A. R., Gomez, R. & Lis, P. Rab29 activation of the Parkinson’s disease-associated LRRK2 kinase. EMBO J. 37, 1–18 (2018).
Prashar, A., Schnettger, L., Bernard, E. M. & Gutierrez, M. G. Rab GTPases in Immunity and Inflammation. Front. Cell. Infect. Microbiol. 7, 435 (2017).
Matheoud, D., Sugiura, A., Bellemare-Pelletier, A., Laplante, A. & Rondeau, C. Parkinson’s disease-related proteins PINK1 and Parkin repress mitochondrial antigen presentation. Cell 166, 314–327 (2016).
International Parkinson’s Disease Genomics Consortium (IPDGC) & Wellcome Trust Case Control Consortium 2 (WTCCC2). A two-stage meta-analysis identifies several new loci for Parkinson’s disease. PLoS Genet. 7, e1002142 (2011).
Foo, J. N., Liu, J. J. & Tan, E. K. Whole-genome and whole exome sequencing in neurological diseases. Nat. Rev. Neurol. 8, 508–517 (2012).
Foo, J. N., Tan, L. C., Irwan, I. D., Au, W. L. & Low, H. Q. Genome-wide association study of Parkinson’s disease in East Asians. Hum. Mol. Genet. 26, 226–232 (2017).
Blauwendraat, C., Heilbron, K., Vallerga, C. L., Bandres-Ciga, S. & von Coelln, R. Parkinson’s disease age at onset genome-wide association study: defining heritability, genetic loci, and alpha-synuclein mechanisms. Mov. Disord. 34, 866–874 (2019).
Aliseychik, M. P., Andreevam, T. V. & Rogaev, E. I. Immunogenetic factors of neurodegenerative diseases: the role of HLA class II. Biochemistry (Mosc) 83, 1104–1116 (2018).
Hamza, T. H., Zabetian, C. P., Tenesa, A., Laederach, A. & Montimurro, J. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat. Genet. 42, 781–785 (2010). This is the first genome-wide association study to identify the association between the HLA locus and the risk of PD.
Nalls, M. A., Pankratz, N., Lill, C. M., Do, C. B. & Hernandez, D. G. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat. Genet. 46, 989–993 (2014).
Zhao, Y., Gopalai, A. A., Ahmad-Annuar, A., Teng, E. W. & Prakash, K. M. Association of HLA locus variant in Parkinson’s disease. Clin. Genet. 84, 501–504 (2013).
Wissemann, W. T., Hill-Burns, E. M., Zabetian, C. P., Factor, S. A. & Patsopoulos, N. Association of Parkinson disease with structural and regulatory variants in the HLA region. Am. J. Hum. Genet. 93, 984–993 (2013).
Hollenbach, J. A., Norman, P. J., Creary, L. E., Damotte, V. & Montero-Martin, G. A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson’s disease. Proc. Natl Acad. Sci. USA 116, 7419–7424 (2019).
Pierce, S. & Coetzee, G. A. Parkinson’s disease-associated genetic variation is linked to quantitative expression of inflammatory genes. PLoS One 12, e0175882 (2017).
Savitt, D. & Jankovic, J. Targeting α-Synuclein in Parkinson’s disease: progress towards the development of disease-modifying therapeutics. Drugs 79, 797–810 (2019). This is an up-to-date review of clinical immunotherapy studies targeting α-synuclein and other targets in PD.
Liu, Y., Xie, X., Xia, L. P., Lv, H. & Lou, F. Peripheral immune tolerance alleviates the intracranial lipopolysaccharide injection-induced neuroinflammation and protects the dopaminergic neurons from neuroinflammation-related neurotoxicity. J. Neuroinflammation 14, 223 (2017).
Huang, Y., Liu, Z., Cao, B. B., Qiu, Y. H. & Peng, Y. P. Treg cells protect dopaminergic neurons against MPP+ neurotoxicity via CD47-SIRPA interaction. Cell. Physiol. Biochem. 41, 1240–1254 (2017).
Herrero, M. T., Estrada, C., Maatouk, L. & Vyas, S. Inflammation in Parkinson’s disease: role of glucocorticoids. Front. Neuroanatomy 9, 32 (2015).
Ren, L., Yi, J., Yang, J., Li, P. & Cheng, X. Nonsteroidal anti-inflammatory drugs use and risk of Parkinson disease: a dose-response meta-analysis. Medicine 97, e12172 (2018).
Poly, T. N., Islam, M. M. R., Yang, H. C. & Li, Y. J. Non-steroidal anti-inflammatory drugs and risk of Parkinson’s disease in the elderly population: a meta-analysis. Eur. J. Clin. Pharmacol. 75, 99–108 (2019). This is an up-to-date meta-analysis of the use of NSAIDs and the risk of PD.
Racette, B. A., Gross, A., Vouri, S. M., Camacho-Soto, A. & Willis, A. W. Immunosuppressants and risk of Parkinson disease. Ann. Clin. Transl. Neurol. 5, 870–875 (2018).
Olesen, M. N., Christiansen, J. R., Petersen, S. V., Jensen, P. H. & Paslawski, W. CD4 T cells react to local increase of alpha-synuclein in a pathology-associated variant-dependent manner and modify brain microglia in absence of brain pathology. Heliyon 4, e00513 (2018).
Huang, Y. R., Xie, X. X., Ji, M., Yu, X. L. & Zhu, J. Naturally occurring autoantibodies against alpha-synuclein rescues memory and motor deficits and attenuates alpha-synuclein pathology in mouse model of Parkinson’s disease. Neurobiol. Dis. 124, 202–217 (2019).
Carta, A. R. & Pisanu, A. Modulating microglia activity with PPAR-γ agonists: a promising therapy for Parkinson’s disease? Neurotox. Res. 23, 112–123 (2012).
Simuni, T., Kieburtz, K., Tilley, B., Elm, J. J. & Ravina, B. Pioglitazone in early Parkinson’s disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol. 14, 795–803 (2015).
Machado, M. M. F., Bassani, T. B., Cóppola-Segovia, V., Moura, E. L. R. & Zanata, S. M. PPAR-y agonist pioglitazone reduces microglial proliferation and NF-kB activation in the substantia nigra in the 6-hydroxydopamine model of Parkinson’s disease. Pharmacol. Rep. 71, 556–564 (2018).
Tamburrino, A., Churchill, M. J., Wan, O., Colino-Sanguino, Y. & Ippolito, R. Cyclosporin promotes neurorestoration and cell replacement therapy in pre-clinical models of Parkinson’s disease. Acta Neuropathol. Commun. 14, 84 (2015).
Van der Perren, A., Macchi, F., Toelen, J., Carlon, M. S. & Maris, M. FK506 reduces neuroinflammation and dopaminergic neurodegeration in an a-synuclein-based rat model for Parkinson’s disease. Neurobiol. Aging 36, 1559–1568 (2015).
McGinnis, G. J. et al. Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model. Oncotarget 8, 9155–9173 (2017).
Prots, I. & Winner, B. Th17 cells: a promising therapeutic target for Parkinson’s disease? Expert. Opin. Ther. Targets 23, 309–314 (2019).
Elgueta, D. et al. Dopamine receptor D3 expression is altered in CD4+ T-cells from Parkinson’s disease patients and its pharmacologic inhibition attenuates the motor impairment in a mouse model. Front. Immunol. 10, 981 (2019).
Czaja, A. J. Immune inhibitory proteins and their pathogenic and therapeutic implications in autoimmunity and autoimmune hepatitis. Autoimmunity 52, 144–160 (2019).
Sun, C., Wei, L., Luo, F., Li, Y. & Li, J. HLA-DRB1 alleles are associated with the susceptibility to sporadic Parkinson’s disease in Chinese Han population. PLoS One 7, e48594 (2012).
Saiki, M., Baker, A., Williams-Gray, C. H., Foltynie, T. & Goodman, R. S. Association of the human leucocyte antigen region with susceptibility to Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 81, 890–891 (2010).
Badres-Ciga, S., Price, T. R., Barrero, F. J., Escamilla-Sevilla, F. & Pelegrina, J. Genome-wide assessment of Parkinson’s disease in a southern Spanish population. Neurobiol. Aging 45, 213.e3–213.e9 (2016).
Chang, K. H., Wu, Y. R., Chen, Y. C., Fung, H. C. & Lee-Chen, G. J. STK39, but not BST1, HLA-DQB1, and SPPL2B polymorphism, is associated with Han-Chinese Parkinson’s disease in Taiwan. Medicine 94, e1690 (2015).
Jamshidi, J., Movafagh, A., Emamalizadeh, B., Zare Bidoki, A. & Manafi, A. HLA-DRA is associated with Parkinson’s disease in Iranian population. Int. J. Immunogenet. 41, 508–511 (2014).
Zhu, R. L., Lu, X. C., Tang, L. J., Huang, B. S. & Yu, W. Association between HLA rs3129882 polymorphism and Parkinson’s disease: a meta-analysis. Eur. Rev. Med. Pharmacol. Sci. 19, 423–432 (2015).
Mo, M. S., Xiao, Y. S., Wu, Z. H., Sun, C. C. & Zhang, L. M. Association analysis of HLA-DRA in Chinese patients with sporadic Parkinson’s disease. Int. J. Physiol. Pahtophysiol. Pharmacol. 7, 185–194 (2015).
Ma, Z. G., Liu, T. W. & Bo, Y. L. HLA-DRA rs3129882A/G poplymorphism was not a risk factor for Parkinson’s disease in Chinese-based populations: a meta-analysis. Int. J. Neurosci. 125, 241–246 (2015).
Schneeberger, A., Mandler, M., Mattner, F. & Schmidt, W. Vaccination for Parkinson’s disease. Parkinsonism Relat. Disord. https://doi.org/10.1016/S1353-8020(11)70006-2 (2012).
Braczynski, A. K., Schulz, J. B. & Bach, J. P. Vaccination strategies in tauopathies and synucleinopathies. J. Neurochem. 143, 467–488 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02216188 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01885494 (2015).
Sardi, S. P., Cedarbaum, J. M. & Brudin, P. Targeted therapies for Parkinson’s disease: from genetics to the clinic. Mov. Disord. 33, 684–696 (2018).
Zella, S. M. A., Metzdorf, J., Ciftci, E., Ostendorf, F. & Muhlack, S. Emerging immunotherapies for Parkinson disease. Neurol. Ther. 8, 29–44 (2019).
No authors listed. ABBV-0805 — Parkinson’s disease. Bioarctic https://www.bioarctic.se/en/ban0805-parkinsons-disease-2498/ (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02095171 (2015).
Jankovic, J., Goodman, I., Safirstein, B., Marmon, T. K. & Schenk, D. B. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-α-Synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol. 75, 1206–1214 (2018).
Schenk, D. B., Koller, M., Ness, D. K., Griffith, S. G. & Grundman, M. First-in-human assessment of PRX002, an anti-alpha-synuclein monoclonal antibody, in healthy volunteers. Mov. Disord. 32, 211–218 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03100149 (2019).
Brys, M., Fanning, L., Hung, S., Ellenbogen, A. & Penner, N. Randomized phase I clinical trial of anti-alpha-synuclein antibody BIIB054. Mov. Disord. 34, 1154–1163 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03318523 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01882010 (2016).
Roser, A. E., Tonges, L. & Lingor, P. Modulation of microglial activity by Rho-kinase (ROCK) inhibition as therapeutic strategy in Parkinson’s disease and amyotrophic lateral sclerosis. Front. Aging Neurosci. 4, 94 (2017).
Martinez, B. & Peplow, P. V. Neuroprotection by immunomodulatory agents in animal models of Parkinson’s disease. Neural Regen. Res. 13, 1493–1506 (2018). This is a detailed review of the studies on immunomodulatory agents in experimental models of PD.
Chandra, G., Rangasamy, S. B., Roy, A., Kordower, J. H. & Pahan, K. Neutralization of RANTES and eotaxin prevents the loss of dopaminergic neurons in a mouse model of Parkinson disease. J. Biol. Chem. 291, 15267–15281 (2016).
E.K.-T. and Y.X.-C. are supported by grants from the Singapore Ministry of Health’s National Medical Research Council STaR (E.K.-T.), PD Clinical translational research, SPARK II, OF LCG 0002 (E.K.-T. and Y.X.-C.), TA Award (Y.X.-C.) and CSA 0021/2017 Award (L.L.-C). The authors thank S. Chan, C. Chan and W. T. Saw from the National Neuroscience Institute, Singapore, for their assistance with editing parts of the manuscript.
The authors declare no competing interests.
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- Expression quantitative trait locus
A genomic locus that explains a fraction of the variation in phenotype.
- False discovery rate
A statistical approach used in multiple hypothesis testing to correct for multiple comparisons.
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Tan, E., Chao, Y., West, A. et al. Parkinson disease and the immune system — associations, mechanisms and therapeutics. Nat Rev Neurol 16, 303–318 (2020). https://doi.org/10.1038/s41582-020-0344-4
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