T cells from patients with Parkinson’s disease recognize α-synuclein peptides

Sulzer, David; Alcalay, Roy N.; Garretti, Francesca; Côté, Lucien J.; Kanter, Ellen; Agin‐Liebes, Julian; Liong, Christopher; McMurtrey, Curtis P.; Hildebrand, William H.; Mao, Xiaobo; Dawson, Valina L.; Dawson, Ted M.; Oseroff, Carla; Pham, John; Sidney, John; Dillon, Myles; Carpenter, Chelsea; Weiskopf, Daniela; Phillips, Elizabeth; Mallal, S.; Peters, Bjoern; Frazier, April; Arlehamn, Cecilia S. Lindestam; Sette, Alessandro

doi:10.1038/nature22815

Cited by 648 publications

(686 citation statements)

References 44 publications

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“…Although the association between PD and the HLA region is complex, it has been suggested that the hits at HLA-DRB6 and HLA-DQA1 could implicate regulation of antigen presentation as a potential mechanism by which the immune response links environmental factors to genetic susceptibility in conferring risk for PD (Kannarkat et al 2015). Indeed, Sulzer et al have recently reported that α -synuclein-derived fragments act as antigenic epitopes displayed by HLA receptors, where both helper and cytotoxic T-cell responses are present in a high percentage of patients when tested (Sulzer et al 2017). …”

Section: A Glimpse Into Much Larger Networkmentioning

confidence: 99%

Genetic risk factors in Parkinson’s disease

et al. 2018

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Over the last two decades, we have witnessed a revolution in the field of Parkinson’s disease (PD) genetics. Great advances have been made in identifying many loci that confer a risk for PD, which has subsequently led to an improved understanding of the molecular pathways involved in disease pathogenesis. Despite this success, it is predicted that only a relatively small proportion of the phenotypic variability has been explained by genetics. Therefore, it is clear that common heritable components of disease are still to be identified. Dissecting the genetic architecture of PD constitutes a critical effort in identifying therapeutic targets and although such substantial progress has helped us to better understand disease mechanism, the route to PD disease-modifying drugs is a lengthy one. In this review, we give an overview of the known genetic risk factors in PD, focusing not on individual variants but the larger networks that have been implicated following comprehensive pathway analysis. We outline the challenges faced in the translation of risk loci to pathobiological relevance and illustrate the need for integrating big-data by noting success in recent work which adopts a broad-scale screening approach. Lastly, with PD genetics now progressing from identifying risk to predicting disease, we review how these models will likely have a significant impact in the future.

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Section: A Glimpse Into Much Larger Networkmentioning

confidence: 99%

Genetic risk factors in Parkinson’s disease

et al. 2018

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“…Accumulated α-synuclein inside dopaminergic neurons acts as a foreign antigen that triggers a T-cell regulated response and subsequent autophagy of dopaminergic neurons (Papachroni et al 2007), which provides a possible explanation for induction of an autoimmune response. Moreover, recently it was reported that T cells from PD patients and healthy controls age-matched differentially recognize and react to certain epitopes of α-synuclein, the main protein component in Lewy Bodies (Sulzer et al, 2017). These studies indicate a role for adaptive autoimmunity in PD.…”

Section: Parkinson’s Disease and The Immune Systemmentioning

confidence: 99%

“…Lymphocyte-activation gene-3 (LAG-3), present on multiple immune cells and a ligand for human leukocyte antigen class II molecules, specifically binds to pre-fibrillary forms of α-synuclein (PFF α-synuclein), and knockout of this gene attenuates PFF α-synuclein-induced neurodegeneration (Mao et al, 2016) Based on the premises that exogenous pre-fibrillary α-synuclein can induce dopaminergic neurodegeneration (Volpicelli-Daley et al, 2011); and that PD T-cells in the CNS respond differentially to α-synuclein peptides presented by HLA (Sulzer et al, 2017), there is sufficient evidence to postulate that α-synuclein may be a link between immune dysfunction and neurodegeneration in PD. This aligns with our hypothesis that there is a potential bidirectional communication between the peripheral (immune) and central dopaminergic systems.…”

Section: Parkinson’s Disease and The Immune Systemmentioning

confidence: 99%

The dopamine transporter: An unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson’s Disease

Mackie

Lebowitz

Saadatpour

et al. 2018

Brain, Behavior, and Immunity

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The second-most common neurodegenerative disease, Parkinson's Disease (PD) has three hallmarks: dysfunctional dopamine transmission due, at least in part, to dopamine neuron degeneration; intracellular inclusions of α-synuclein aggregates; and neuroinflammation. The origin and interplay of these features remains a puzzle, as does the underlying mechanism of PD pathogenesis and progression. When viewed in the context of neuroimmunology, dopamine also plays a role in regulating peripheral immune cells. Intriguingly, plasma dopamine levels are altered in PD, suggesting collateral dysregulation of peripheral dopamine transmission. The dopamine transporter (DAT), the main regulator of dopaminergic tone in the CNS, is known to exist in lymphocytes and monocytes/macrophages, but little is known about peripheral DAT biology or how DAT regulates the dopaminergic tone, much less how peripheral DAT alters immune function. Our review is guided by the hypothesis that dysfunctional peripheral dopamine signaling might be linked to the dysfunctional immune responses in PD and thereby suggests a potential bidirectional communication between central and peripheral dopamine systems. This review seeks to foster new perspectives concerning PD pathogenesis and progression.

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“…Notably, there are numerous reciprocal links between immune cell activation and alpha-synuclein aggregation. For example, alpha-synuclein fragments activate immune cells in various PD models [34], and are suggested to be one of the triggers for microglial activation in the brains of PD patients [35]. The GI tract of PD patients has elevated numbers of proinflammatory microbes, and these have been suggested to promote microglial activation and alpha-synuclein aggregation in the brain via microbial metabolites (short chain fatty acid signaling) [36].…”

Section: Editorialmentioning

confidence: 99%

Alpha-Synuclein to the Rescue: Immune Cell Recruitment by Alpha-Synuclein during Gastrointestinal Infection

Labrie

Brundin²

2017

J Innate Immun

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Intraneuronal accumulation of misfolded alpha-synuclein in the central and peripheral nervous systems is strongly linked to Parkinson disease (PD) and other related synucleinopathies. In rare inherited forms of PD, point mutations or gene multiplications mediate the formation of alpha-synuclein protein aggregates. However, in most PD cases it is presumed that the combined effects of ageing and environmental factors drive the formation of alpha-synuclein aggregates. Despite advances regarding alpha-synuclein pathobiology, the normal functions of this protein and factors that regulate its expression are not well understood. We discuss a recent study reporting that viral infection induces alpha-synuclein expression in neurons of the gastrointestinal tract. Alpha-synuclein levels increased during norovirus infection in the duodenum of children. In an in vitro paradigm, monomeric and oligomeric alpha-synuclein acted as chemoattractants for neutrophils and monocytes, and promoted the maturation of dendritic cells. This suggests that alpha-synuclein facilitates immune responses to infection. We explore the possibility that intestinal infections, and associated inflammation, place individuals at increased risk of PD by increasing alpha-synuclein levels and promoting the formation of alpha-synuclein aggregates that propagate in a prion-like fashion via the vagal nerve to the brainstem.

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T cells from patients with Parkinson’s disease recognize α-synuclein peptides

Cited by 648 publications

References 44 publications

Genetic risk factors in Parkinson’s disease

Genetic risk factors in Parkinson’s disease

The dopamine transporter: An unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson’s Disease

Alpha-Synuclein to the Rescue: Immune Cell Recruitment by Alpha-Synuclein during Gastrointestinal Infection

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