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Gene dysfunction mediates immune response to Dopaminergic degeneration in Parkinson’s disease Zhigang Jiao, Wenlong Zhang, Chaojun Chen, Xiaoqin Zhu, Xiang Chen, Miaomiao Zhou, Guoyou Peng, Hanqun Liu, Jiewen Qiu, Yuwan Lin, Shuxuan Huang, Mingshu Mo, Xinling Yang, Shaogang Qu, and Pingyi Xu ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00373 • Publication Date (Web): 05 Oct 2018 Downloaded from http://pubs.acs.org on October 6, 2018
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ACS Chemical Neuroscience
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Gene dysfunction mediates immune response to Dopaminergic
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degeneration in Parkinson’s disease
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Zhigang Jiao1,2#, Wenlong Zhang3#, Chaojun Chen4#, Xiaoqin Zhu5, Xiang Chen3,
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Miaomiao Zhou3, Guoyou Peng3, Hanqun Liu3, Jiewen Qiu3, Yuwan Lin3, Shuxuan
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Huang3, Mingshu Mo3, Xinling Yang6*, Shaogang Qu1,2*, Pingyi Xu3*
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1Central
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China
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2Key
Laboratory, Shunde Hospital, Southern Medical University, Foshan 528300,
Laboratory of Mental Health of the Ministry of Education, Southern Medical
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University
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3Department
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Guangzhou 510120, China.
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4Department
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Guangdong 510800, China.
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5Guangzhou
Medical University, Guangzhou 511436, China.
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6Department
of Neurology, the Third Affiliated Hospital of Xinjiang Medical University,
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Urumqi 830011, China.
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#These authors contributed equally to this work.
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*To whom correspondence should be addressed.
of Neurology, the First Affiliated Hospital of Guangzhou Medical University,
of Neurology, Guangzhou Chinese Medical Integrated Hospital (Huadu),
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E-mail: Pingyi Xu:
[email protected]; Shaogang Qu:
[email protected]; Xinling Yang:
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[email protected];
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ABSTRACT
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Many publications reported the genetic dysfunction mediates abnormal immune
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responses in brain, which is important for the development of neurodegenerative diseases,
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especially for Parkinson disease (PD). This immune disorder resulted in the subsequent
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inflammatory reaction which stimulates microglia or other immune cells to secrete
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cytokines and chemokines, disturbs the proportion of peripheral blood lymphocyte subsets
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contributing to Dopaminergic (DA) neuron apoptosis. Furthermore, the abnormal immune
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related signal pathways caused by genetic variants promotes chronic inflammatory to
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destroy the blood-brain barrier, which infiltrates different molecules and blood cells into
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the central nervous system (CNS) and exert neural toxicity on DA neurons. As a result, the
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inflammatory reaction in CNS accelerates the progression of Parkinson diseases and
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promotes α-synuclein aggregation and diffusion among DA neurons in the procession of
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Parkinson disease. Thus, for disease evaluation, the genetic mediated abnormal immune
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response in PD may be assessed on the multiple immune molecules, inflammatory factors,
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as well as the ratio of lymphocyte subsets from PD patient’s peripheral blood as potential
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biomarkers.
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Keywords: Parkinson’s disease, genetic variants, immune response, DA degeneration
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INTRODUCTION
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Parkinson’s disease (PD) is the second most common aging related neurodegenerative
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disorder with accumulation of α-synuclein (α-syn) being the pathological hallmark of the
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disease in the world.1 In addition to aging, there is strong evidence that the interaction of
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genetic factors with environmental elements affects the development of PD.2 It has been
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reported that the clinical features of PD may be based on the different function-link regions
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of brain caused by gene variants and that PD displays complex motor and non-motor
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symptoms, but the underlying reason for the clinical diversity of PD is not fully
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understood.3 Recently, a large number of studies on cell biologic, biochemical, genetic,
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pathologic and immunologic investigations revealed that the abnormal immune response
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and its subsequent chronic inflammatory reaction in the patients’ central nervous system
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(CNS) play crucial roles on the degeneration of Dopaminergic neurons.4 The
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phosphorylation of α-syn deposited in patients’ brain is erroneously recognized as the
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antigens to induce abnormal immune response and results in the loss of DA neurons. But
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how occurs the immune events and whether it can be regulated are still a greater challenge.
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Only to understanding the mechanism of immune response and its subsequent neuro-
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inflammation conducted by genetic variants on neural degeneration, it could be possible to
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discover the role of the immune dysfunction on the pathogenesis of Parkinson’s disease.
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ASSOCIATION OF GENE VARIANTS WITH PARKINSON DISEASE
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It is well known that gene mutation causing immune system dysfunction induces cell
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proliferation such as microglia or lymphocytes to secrete a large number of inflammatory
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factors, and results in the damage of the central nervous system. A screen of genome wide
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association studies (GWAS) provided significant evidence that immune related genes play
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important roles on the pathogenesis of PD (Table 1).5-8 Among them the HLA-DR genes
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are most frequently concerned because the allele of these gene may increase the risk of
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Parkinson disease. The products of HLA-DR genes are the crucial regulators of the cellular
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immune system and present peptide antigens to the immune system to elicit or suppress T3
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(helper)-cell activation that eventually product antibodies against the antigen-presentation
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or stimulate CD8+ T cytotoxicity on neurons. For example, a positive association was
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confirmed between PD and HLA-B*07:02, DRB1*15:01, DQB1*06:02, but negative
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association with DRB1*04:04, respectively.6, 9, 10 It is important to note that many HLA-
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DR SNPs vary ethnically and regionally (Supplementary Table 1), among them HLA-
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DRB1*15:01, DQB1*03:04 and DRB5*01:01, seem to be closely related to PD in Europe
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and America,9 but not in China. A GWAS study conducted in Europe confirmed that SNP
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of rs3129882 is closely related to the risk of PD. DNA analysis revealed that the rs3129882
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polymorphism is at intron 1 of HLA-DRA response to gene splicing as a cis component
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which involves the antigen presentation of α-syn.8 Guo et al. reported that the rs3129882
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of HLA-DRA may be related to the Chinese population with PD,11 but no strong correlation
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was detected in Japanese and Taiwanese PD populations.12 There is currently not enough
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data to support the idea that HLA-DRA rs3129882 increases the risk of PD in South
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Chinese populations, although the genotypic frequency of HLA-DRB1*0301 seems higher
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in Chinese PD males compared to females. Meanwhile, based on our screening data for
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Southern Chinese population, we pointed out that a possible associations of HLA-A*2,
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HLA-B*17, HLA-DQB1*06 and HLA-DRB1*03 with PD was positive, as similarly
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reported in Europe.6 Other reports also revealed that HLA-DRB1*15:01, DQB1*03:04 and
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DRB5*01:01 are closely related to the risk of PD in Europeans and Americans,9 but no
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investigations have been started in China. Therefore, we reasonably considered that the
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differences in SNPs of HLA may be associated with ethnic regions related to
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neurodegenerative diseases, especially in Parkinson disease.
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The latest discovery showed that lymphocyte-activation gene 3 （LAG-3）gene is mainly
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involved in the antigen-presentation of α-syn. LAG-3 gene encodes a membrane protein,
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negatively regulates T lymphocyte-mediated antigen presentation of α-syn, is responsible
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for the intracellular endocytosis of abnormal proteins, and responds to the aggregation and
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transmission of α-syn between cells. It was reported that the dysfunction of LAG-3 4
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mediates the transmission of α-syn between DA neurons by phagocytosis.13 After transcript
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splicing, soluble LAG-3 (sLAG-3) is the remaining product of LAG-3, which is regulated
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by ADAM10 and ADAM17 lyase targeted at the D4 domain of the gene.14 sLAG-3 can
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directly bind to MHC molecules at the surface of the immature DC cells (Dendritic Cell)
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to promote DC cell maturation and differentiation via the phosphorylation pathway of
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PLCr2, IP3/Akt, p42/44ERK, p38MAPK. This pathway enhances the antigen presentation
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of α-syn in CNS conducted by the immune cells such as microglia or monocytes to secrete
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the inflammatory factors such as TNF-α and other inflammatory mediators.15-17 Based on
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the scale screening of Chinese PD populations, we found that LAG-3 is not only expressed
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in the activated T cells and NK cells, but also in the DA neurons of CNS (data unpublished).
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For example, LAG-3 expression was detected in TH+ cell membrane, but no LAG-3 protein
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was detected in the astrocytes and microglia of mouse brains. In an experiment for α-syn
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transmission between the cultured cells, we found that iron impaired the endocytosis of
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neurons and promoted α-syn into aggregation and transmission from cell to cell by
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inhibiting autophagosome-lysosome fusion and nuclear translocation of transcription
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factor EB (TFEB) factors.18 But whether Fe/TFEB is involved in the antigen-presentation
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of α-syn mediated by LAG-3/MHC pathway remains to be investigated.
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There was a report about LAG-3 rs870849 closely related to Multiple sclerosis (MS)
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in Europe.19 We preliminarily found that the LAG-3 rs951818C/A allele is higher, while
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the allele frequency of rs870849 is lower in 487 female Chinese PD patients, and that the
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levels of sLAG in cerebrospinal fluid of PD patients were increased compared to other
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CNS disease controls（P
