NK cells clear α-synuclein and the depletion of NK cells exacerbates synuclein pathology in a mouse model of α-synucleinopathy

Earls, Rachael H.; Menees, Kelly B.; Chung, Julianne; Gutekunst, Claire‐Anne; Lee, Hyun Joon; Hazim, Manuel G.; Rada, Balázs; Wood, Levi B.; Lee, Jaekyung

doi:10.1073/pnas.1909110117

Cited by 96 publications

(141 citation statements)

References 75 publications

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“…That particular preclinical model utilized α-syn transgenic mice that over-express human α-syn with the A53T mutation, and combined it with an injection of human α-syn PFFs into the dorsal striatum. The depletion of NK cells in this model of α-syn-induced pathology suggests that NK cells can contribute to the clearance of α-syn aggregates, or prevent their formation [75]. The mice we used in our study also have deficiencies in NK cells.…”

Section: Discussionmentioning

confidence: 94%

“…They are implicated in diseases of autoimmunity and within the CNS, and can interact with microglia [74]. Recently, it was reported that systemic depletion of NK cells in a preclinical model of PD exacerbated α-syn pathology [75]. That particular preclinical model utilized α-syn transgenic mice that over-express human α-syn with the A53T mutation, and combined it with an injection of human α-syn PFFs into the dorsal striatum.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, we found that phosphorylated α-syn was increased in multiple brain regions in both NOD/ShitLtJ mice and NSG mice when compared to wildtype mice in Figure 1. In light of the findings mentioned above [75], a driver of this difference between wildtype and the mice on the NOD background could also be the dysfunction or absence of NK cells.…”

Section: Discussionmentioning

confidence: 99%

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T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

George¹,

Tyson²,

Rey

et al. 2020

Preprint

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α-Synuclein (α-syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of αsynucleinopathies, such as Parkinson's disease (PD) and multiple system atrophy (MSA). Other hallmarks include activation of microglia, elevation of pro-inflammatory cytokines, as well as the activation of T and B cells.These immune changes point towards a dysregulation of both the innate and the adaptive immune system. T cells have been shown to recognize epitopes derived from α-syn and altered populations of T cells have been found in PD and MSA patients, providing evidence that these cells can be key to the pathogenesis of the disease.To study the role of the adaptive immune system with respect to α-syn pathology, we injected human α-syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated α-syn pathology as well as microgliosis. Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated α-syn pathology in the substantia nigra. We also reconstituted T and B cell populations in the NSG mice with cells isolated from a wildtype mouse spleen. Interestingly, reconstituting the T cell population decreased the accumulation of α-syn pathology and resulted in persistent microgliosis when compared to non-transplanted mice; reconstitution of B cells did not alter the nigral neuropathology. Our work provides experimental evidence that T cells play a role in the pathogenesis of α-synucleinopathies.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

George¹,

Tyson²,

Rey

et al. 2020

Preprint

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“…Indeed, it has been shown that striatal injection of a-Syn PFFs but not monomers in WT mice can trigger neuroinflammation by increasing peripheral immune cells infiltration in the CNS (Earls et al, 2019). Apparently, this immune reaction would precede the dopaminergic neurodegeneration (Harms et al, 2017) but, it cannot be excluded that the magnitude and the efficacy of the immune reaction can also modulate the spread of the pathology observed as it was recently suggested by (Earls et al, 2020).…”

Section: Propagation Of Alpha-synuclein: Evidence and Considerationsmentioning

confidence: 96%

Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

et al. 2020

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Alpha-synuclein (a-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD is characterized by the loss of dopaminergic neuronal cells in the substantia nigra pars compacta and the abnormal accumulation and aggregation of a-Syn in the form of Lewy bodies and Lewy neurites. More precisely, the aggregation of a-Syn is associated with the dysfunctionality and degeneration of neurons in PD. Moreover, mutations in the SNCA gene, which encodes a-Syn, cause familial forms of PD and are the basis of sporadic PD risk. Given the role of the a-Syn protein in the pathology of PD, animal models that reflect the dopaminergic neuronal loss and the widespread and progressive formation of a-Syn aggregates in different areas of the brain constitute a valuable tool. Indeed, animal models of PD are important for understanding the molecular mechanisms of the disease and might contribute to the development and validation of new therapies. In the absence of animal models that faithfully reproduce human PD, in recent years, numerous animal models of PD based on a-Syn have been generated. In this review, we summarize the main features of the a-Syn pre-formed fibrils (PFFs) model and recombinant adenoassociated virus vector (rAAV) mediated a-Syn overexpression models, providing a detailed comparative analysis of both models. Here, we discuss how each model has contributed to our understanding of PD pathology and the advantages and weakness of each of them. Significance: Here, we show that injection of a-Syn PFFs and overexpression of a-Syn mediated by rAAV lead to a different pattern of PD pathology in rodents. First, a-Syn PFFs models trigger the Lewy body-like inclusions formation in brain regions directly interconnected with the injection site, suggesting that there is an inter-neuronal transmission of the a-Syn pathology. In contrast, rAAV-mediated a-Syn overexpression in the brain limits the a-Syn aggregates within the transduced neurons. Second, phosphorylated a-Syn inclusions obtained with rAAV are predominantly nuclear with a punctate appearance that becomes diffuse along the neuronal fibers, whereas a-Syn PFFs models lead to the formation of cytoplasmic aggregates of phosphorylated a-Syn reminiscent of Lewy bodies and Lewy neurites.

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“…Therefore, immunomodulatory-based approaches aimed at halting the propagation and burden of extracellular α-syn, and in turn diminishing the inflammatory response, are currently being tested as a therapeutic for PD and related synucleinopathies (reviewed in 23 ). Recently, it was discovered that natural killer (NK) cells efficiently internalize and degrade α-syn aggregates via the endosomal/lysosomal pathway, a novel and highly relevant function of NK cells in synucleinopathies 24 . The number of circulating NK cells in PD patients is increased compared to non-PD controls 25 .…”

Section: Introductionmentioning

confidence: 99%

The role of natural killer cells in Parkinson’s disease

Earls

Lee

2020

Exp Mol Med

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Numerous lines of evidence indicate an association between sustained inflammation and Parkinson’s disease, but whether increased inflammation is a cause or consequence of Parkinson’s disease remains highly contested. Extensive efforts have been made to characterize microglial function in Parkinson’s disease, but the role of peripheral immune cells is less understood. Natural killer cells are innate effector lymphocytes that primarily target and kill malignant cells. Recent scientific discoveries have unveiled numerous novel functions of natural killer cells, such as resolving inflammation, forming immunological memory, and modulating antigen-presenting cell function. Furthermore, natural killer cells are capable of homing to the central nervous system in neurological disorders that exhibit exacerbated inflammation and inhibit hyperactivated microglia. Recently, a study demonstrated that natural killer cells scavenge alpha-synuclein aggregates, the primary component of Lewy bodies, and systemic depletion of natural killer cells results in exacerbated neuropathology in a mouse model of alpha-synucleinopathy, making them a highly relevant cell type in Parkinson’s disease. However, the exact role of natural killer cells in Parkinson’s disease remains elusive. In this review, we introduce the systemic inflammatory process seen in Parkinson’s disease, with a particular focus on the direct and indirect modulatory capacity of natural killer cells in the context of Parkinson’s disease.

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NK cells clear α-synuclein and the depletion of NK cells exacerbates synuclein pathology in a mouse model of α-synucleinopathy

Cited by 96 publications

References 75 publications

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

The role of natural killer cells in Parkinson’s disease

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