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T Cells Limit Accumulation of Aggregate Pathology Following Intrastriatal Injection of α-Synuclein Fibrils.

ABSTRACT:

Background

α-Synuclein (α-syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of α-synucleinopathies, 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.ObjectiveTo study the role of the adaptive immune system with respect to α-syn pathology.

Methods

We injected human α-syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated α-syn pathology, proteinase K-resistant α-syn pathology and microgliosis in the striatum, substantia nigra and frontal cortex. We also assessed the impact of adoptive transfer of naïve T and B cells into PFF-injected immunocompromised mice.

Results

Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated α-syn pathology in the substantia nigra. Reconstituting the T cell population decreased the accumulation of phosphorylated α-syn pathology and resulted in persistent microgliosis in the striatum when compared to non-transplanted mice.

Conclusion

Our work provides evidence that T cells play a role in the pathogenesis of experimental α-synucleinopathy.

SUBMITTER: George S

PROVIDER: S-EPMC8150548 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague-Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting that PFF-induced pathology exhibits properties similar to human LBs. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time-point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that α-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-synucleinopathy in rats.

Project description:IntroductionAccurate demonstration of phosphorylated α-synuclein aggregation and propagation, progressive nigrostriatal degeneration and motor deficits will help further research on elucidating the mechanisms of Parkinson's Disease. α-synucleinN103 and tauN368, cleaved by activated asparagine endopeptidase in Parkinson's Disease, robustly interacted with each other and triggered endogenous α-synuclein accumulation in a strong manner. However, the detailed pathophysiological process caused by the complex remains to be established.MethodsIn this study, rats were unilaterally inoculated with 15 or 30 μg of this complex or vehicle (phosphate buffered saline, PBS). Over a 6-month period post injection, we then investigated the abundance of pSyn inclusions, nigrostriatal degeneration, and changes in axonal transport proteins to identify the various dynamic pathological changes caused by pSyn aggregates in the nigrostriatal system.ResultsAs expected, rats displayed a dose-dependent increase in the amount of α-synuclein inclusions, and progressive dopaminergic neurodegeneration was observed throughout the study, reaching 30% at 6 months post injection. Impairments in anterograde axonal transport, followed by retrograde transport, were observed prior to neuron death, which was first discovered in the PFFs model.DiscussionThe current results demonstrate the value of a novel rat model of Parkinson's disease characterized by widespread, "seed"-initiated endogenous α-Syn pathology, impaired axonal transport, and a neurodegenerative cascade in the nigrostriatal system. Notably, the present study is the first to examine alterations in axonal transport proteins in a PFF model, providing an appropriate foundation for future research regarding the mechanisms leading to subsequent neurodegeneration. As this model recapitulates some essential features of Parkinson's disease, it provides an important platform for further research on specific pathogenic mechanisms and pre-clinical evaluations of novel therapeutic strategies.