Biology subjects

Brundin, P.

Publications and source records attributed to Brundin, P..

At least 19 recordsLinked to original sources

bioRxiv2026

Neuroinflammation is an early pathological process in a mouse model of prodromal Parkinsons disease

Approximately 90% of Parkinson's disease (PD) patients exhibit olfactory deficits, which often precedes motor symptoms by years, and are a robust predictor for PD and subsequent cognitive decline. Pathological changes in the PD olfactory system, particularly synuclein (Syn) pathology in the olfactory bulb (OB) and severe involvement of the anterior olfactory nucleus (AON), are distinct from normal aging. However, the causal link between Syn aggregation and functional impairment, potentially involving cytotoxicity and neuroinflammation, remains elusive. To investigate these early pathological events, we utilized a prodromal PD model that we have previously characterized, involving the unilateral OB injection of Syn preformed fibrils (PFF) in wild-type mice. This triggers the transneuronal spread of pathogenic Syn, and olfactory dysfunction starting at 1-month post-injections. Here we report on neuropathological and inflammatory events 1-3 month following injection of PFFs into the OB. Following PFF injection, Syn pSer129 pathology progressively accumulated bilaterally in the AON and ipsilateral in the piriform cortex (PCX) over three months. Stereological quantification revealed no significant neuronal loss in the AON or PCX during this 1-3 month interval, indicating that olfactory impairment precedes overt neurodegeneration. Instead, we identified the upregulation of pro-inflammatory genes (Il-1{beta} ; and Il-6), significant microglial reactivity, and sustained astrogliosis within olfactory structures. These findings identify neuroinflammation as a key early mediator linking Syn pathology to olfactory dysfunction in the absence of neuronal loss. This suggests a critical window for therapeutic intervention and highlights neuroinflammatory markers as potential biomarkers for the prodromal phase of PD.

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bioRxiv2026

α-Synuclein Seeding in Dopaminergic Neurons Transplanted into the Putamen of Parkinson's Disease Patients

Healthy embryonic neurons grafted into the putamen of Parkinson's disease (PD) patients start to develop Lewy pathology 10 years after transplantation. It remains unclear whether this pathology is initiated by the spread of host-derived -synuclein (syn) aggregates which seed aggregation in the grafted cells or arises independently from a hostile PD environment (e.g., chronic inflammation). To distinguish these possibilities, we identified syn seeding sites in the human brain using a multiplex in situ seed immunodetection (isSID) assay. In PD and dementia with Lewy bodies (DLB), isSID labeled a subset of Lewy pathology (LP) as puncta along neurites and within inclusions. In multiple system atrophy (MSA), isSID labeled Papp-Lantos bodies and microglia. In progressive supranuclear palsy (PSP), isSID labeled tufted astrocytes. isSID labeled neuromelanin in the substantia nigra independent of diagnosis. In 16- and 27-year intraputamenal neuronal grafts, isSID labeled within and proximal to Lewy pathology, as well as outside the grafted tissue. Younger grafts (18 months and 4 years) lacked Lewy pathology. In the 18-month graft, isSID labeled grafted neurons; at 4 years, isSID was confined to amorphous deposits in the graft and was absent from tyrosine hydroxylase-positive grafted neurons. In conclusion, syn seeding is detectable in grafted neurons before and during LP formation. Because seeding accompanies melanization, but is not explained by melanization alone, these findings support host-derived seeds as a contributor to graft pathology.

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bioRxiv2025

Aggregation-prone alpha-synuclein proteoforms and dysregulated molecular signatures in the vermiform appendix of synucleinopathy patients

Synucleinopathies, including Parkinsons disease, are neurodegenerative diseases characterized by intracellular inclusions containing the amyloidogenic protein alpha-synuclein. While classically considered to be brain disorders, increasing evidence suggests involvement of the gut, with alpha-synuclein aggregates potentially propagating to the brain via the vagus nerve. Evidence also suggests that the vermiform appendix is particularly susceptible to alpha-synuclein aggregation, and appendectomy impacts the onset of Parkinsons disease. However, the mechanisms underlying the aggregation of alpha-synuclein in the vermiform appendix remains poorly understood. To explore this, we assessed aggregation properties in postmortem appendix tissues from healthy controls and synucleinopathy patients using the alpha-synuclein seed amplification assay (alpha-synuclein-SAA) and performed total RNA sequencing alongside differential bisulfite-hybridization-based DNA methylation analysis in the same tissues to investigate the molecular underpinnings. Moreover, we determined alpha-synuclein cleavage patterns by cataloging soluble alpha-synuclein proteoforms from postmortem substantia nigra and post-surgical appendix tissues using top-down mass spectrometry (TD-MS). Alpha-synuclein-SAA was positive in appendix samples for 68.75% of synucleinopathy patients and 6.6% of controls. Genomic profiling revealed dysregulated expression of genes linked to protein folding/degradation, immune/inflammatory responses, and ciliary dynamics in synucleinopathy appendix tissues. TD-MS identified 65 distinct alpha-synuclein proteoforms in the substantia nigra and appendix, with 9 unique to the appendix. Further, in silico modeling revealed higher aggregation propensity of alpha-synuclein proteoforms in the appendix versus substantia nigra. Together, our findings suggest that a tissue environment of alpha-synuclein dysproteostasis in the appendix has the potential to contribute to the development of synucleinopathies. One Sentence SummaryAppendixes from synucleinopathy patients show altered gene expression, unique -syn proteoforms, and higher aggregation propensity than substantia nigra.

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bioRxiv2025

Whole-genome DNA methylation profiling in COVID-19 positive patients reveals alterations in pathways linked to neurological dysfunction

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA betacoronavirus, causing coronavirus disease-19 (COVID-19). Infection with SARS-CoV-2 can result in a broad spectrum of clinical outcomes, ranging from asymptomatic or mild to a severe, deadly illness. Emerging evidence suggests SARS-CoV-2 affects host gene regulation through epigenetic mechanisms, such as DNA methylation, potentially contributing to immune dysregulation and post-acute sequelae, including neurological and psychiatric disorders. However, the extent and functional relevance of these epigenetic changes remain uncertain. Methods and resultsWe employed whole-genome bisulfite sequencing to profile DNA methylation in peripheral blood from SARS-CoV-2-positive patients across a spectrum of symptom severity, ranging from asymptomatic to severe (n=101), in comparison to SARS-CoV-2-negative individuals (n=105). We observed a widespread hypomethylation in the genomes of infected individuals, which was more pronounced in severe cases. Notably, we identified differentially methylated genes in patients with mild (19 genes), moderate (19 genes), and severe (35 genes) symptoms. These genes included those involved in canonical immune responses as well as known to be linked to neurodegenerative diseases. Subsequent pathway enrichment analysis further supported the significant association between the differentially methylated genes and those implicated in Alzheimers and Parkinsons disease, as well as neuropsychiatric conditions, suggesting potential epigenetic links between acute SARS-CoV-2 infection and long-term neurological outcomes. This is one of the first studies to comprehensively map severity-stratified genome-wide DNA methylation changes in COVID-19 patients. ConclusionOur findings underscore the potential importance of epigenetic regulation in the acute responses to SARS-CoV-2 infection and highlight an overlap with epigenetic mechanisms relevant for neuropsychiatric disease processes.

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bioRxiv2024

Tet2 loss suppress α-synuclein pathology by stimulating ciliogenesis

There are no approved treatments that slow Parkinsons disease (PD) progression and therefore it is important to identify novel pathogenic mechanisms that can be targeted. Loss of the epigenetic marker, Tet2 appears to have some beneficial effects in PD models, but the underlying mechanism of action is not well understood. We performed an unbiased transcriptomic analysis of cortical neurons isolated from patients with PD to identify dysregulated pathways and determine their potential contributions to the disease process. We discovered that genes associated with primary cilia, non-synaptic sensory and signaling organelles, are upregulated in both early and late PD patients. Enhancing ciliogenesis in primary cortical neurons via sonic hedgehog signaling suppressed the accumulation of -synuclein pathology in vitro. Interestingly, deletion of Tet2 in mice also enhanced the expression of primary cilia and sonic hedgehog signaling genes and rescued the accumulation of -synuclein pathology and dopamine neuron degeneration in vivo. Our findings demonstrate the crucial role of Tet2 loss in regulating ciliogenesis and potentially affecting the progression of PD pathology.

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bioRxiv2023

Human Endogenous Retrovirus Expression is Dynamically Regulated in Parkinson's Disease

Parkinsons disease (PD) is a progressive, debilitating neurodegenerative disease that afflicts approximately every 1000th individual. Recently, activation of genomic transposable elements (TE) has been suggested as a potential driver of PD onset. However, it is unclear where, when, and to what extent TEs are dysregulated in PD. Here, we performed a multi-tissue transcriptional analysis of multiple patient cohorts and identified TE transcriptional activation as a hallmark of PD. We find that PD patients exhibit up-regulation primarily of human endogenous retrovirus (HERV) transcripts in prefrontal cortex tissue, prefrontal neurons as well as in blood, and we demonstrate that TE activation in the blood is highest at the time of PD diagnosis. Supporting a potentially causal association between ERV dysregulation and PD heterogeneity, reduced gene dosage of the TE repressor Trim28 triggers transcriptional changes highly correlated to those measured in animal models of synucleinopathy (PFF-injection), and importantly, to those exhibited by patients themselves. These data identify ERV up-regulation as a common feature of central and peripheral PD etiology, and highlight potential roles for Trim28-dependent TEs in stratifying and monitoring PD and treatment compliance.

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bioRxiv2022

Increased levels of circulating neurotoxic metabolites in patients with mild Covid19

SARS-CoV-2 corona virus causes a multi-faceted and poorly defined clinical and pathological phenotype involving hyperinflammation, cytokine release, and long-term cognitive deficits, with an undefined neuropathological mechanism. Inflammation increases the activity of the kynurenine pathway, which is linked to neurodegenerative and psychiatric disorders. We sought to determine whether the kynurenine pathway is impacted in patients with mild COVID-19, leading to elevated neurotoxic metabolites in blood, and whether such changes are associated with pro-inflammatory cytokines. Serum samples were taken from 150 patients and analyzed by ELISA and ultra-high performance liquid chromatography (UHPLC). The data were analyzed using multiple linear regression models adjusted for age and sex. We found increased levels of kynurenine, quinolinic acid and 3-hydroxykynurenine in serum from patients with mild COVID-19, together with increased levels of IL-6, ICAM-1, VCAM-1 and neopterin. The levels of neurotoxic metabolites were significantly associated with key inflammatory cytokines including IL-6 and TNF. The COVID-19 risk-factor hypertension was associated with the highest levels of neurotoxic metabolites in plasma. These neuroactive metabolites could be part of the pathological mechanisms underlying cognitive impairment during and post-COVID and should be explored as potential biomarkers for long-COVID symptoms.

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bioRxiv2022

Genetic and pharmacological reduction of CDK14 mitigates synucleinopathy

Parkinsonas disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of -Synuclein (-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the -Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress -Syn replicate several features of PD. Decreasing total -Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of -Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of -Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the -Syn preformed fibrils (PFF)-induced PD mouse model. We found that loss of Cdk14 mitigates the grip strength deficit of PFF-treated mice and ameliorates PFF-induced cortical -Syn pathology, indicated by reduced numbers of pS129 -Syn-containing cells. In primary neurons, we found that Cdk14 depletion protects against the propagation of toxic -Syn species. We further validated these findings on pS129 -Syn levels in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractable in vitro and in vivo. We found that CDK14 inhibition decreases total and pathologically aggregated -Syn in human neurons, in PFF- challenged rat neurons and in the brains of -Syn-humanized mice. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy.

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bioRxiv2022

A novel automated morphological analysis of microglia activation using a deep learning assisted model

There is growing evidence for the key role of microglial activation in brain pathophysiology. Consequently, there is a need for efficient automated methods to measure the morphological changes distinctive of microglia functional states in research settings. Currently, many commonly used automated methods can be subject to sample representation bias, time consuming imaging, specific hardware requirements, and difficulty in maintaining an accurate comparison across research environments. To overcome these issues, we use commercially available deep learning tools (Aiforia(R) Cloud (Aifoira Inc., Cambridge, United States) to quantify microglial morphology and cell counts from histopathological slides of Iba1 stained tissue sections. We provide evidence for the effective application of this method across a range of independently collected datasets in mouse models of viral infection and Parkinsons disease. Additionally, we provide a comprehensive workflow with training details and annotation strategies by feature layer that can be used as a guide to generate new models. In addition, all models described in this work are shared within the Aiforia(R) platform and are available for study-specific adaptation and validation.

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bioRxiv2022

Synaptic Location Is a Determinant of the Detrimental Effects of α-Synuclein Pathology to Glutamatergic Transmission in the Basolateral Amygdala

The presynaptic protein -synuclein (Syn) has been suggested to be involved in the pathogenesis of Parkinsons disease (PD). In PD, the amygdala is prone to develop insoluble Syn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how Syn aggregates affect amygdala function is unknown. In this study, we examined Syn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that Syn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1+) terminals in mouse BLA, which is consistent with higher levels of Syn expression in vGluT1+ glutamatergic neurons in the cerebral cortex relative to the vGluT2+ glutamatergic neurons in the thalamus. We found that Syn aggregation selectively decreased the cortico-BLA, but not the thalamo-BLA, transmission; and that cortico-BLA synapses displayed enhanced short-term depression upon repetitive stimulation. In addition, using confocal microscopy, we found that vGluT1+ axon terminals exhibited decreased levels of soluble Syn, which suggests that lower levels of soluble Syn might underlie the enhanced short-term depression of cortico-BLA synapses. In agreement with this idea, we found that cortico-BLA synaptic depression was also enhanced in Syn knockout mice. In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of Syn and these changes might be relevant to the perturbed cortical control of the amygdala that has been suggested to play a role in psychiatric symptoms in PD.

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bioRxiv2021

Distribution of phosphorylated alpha-synuclein in non-diseased brain implicates olfactory bulb mitral cells in synucleinopathy pathogenesis

Synucleinopathies are neurodegenerative diseases characterized by pathological inclusions called "Lewy pathology" (LP) that consist of aggregated alpha-synuclein predominantly phosphorylated at serine 129 (PSER129). Despite the importance for understanding disease, little is known about the endogenous function of PSER129 or why it accumulates in disease. Here we conducted several observational studies using a sensitive tyramide signal amplification (TSA) technique to determine PSER129 distribution and function in the non-diseased mammalian brain. In wild-type non-diseased mice, PSER129 was detected in the olfactory bulb (OB) and several brain regions across the neuroaxis (i.e., OB to brain stem). In contrast, PSER129 immunoreactivity was not observed in any brain region of alpha-synuclein knockout mice. We found evidence of PSER129 positive structures in OB mitral cells of non-diseased mice, rats, non-human primates, and healthy humans. Using TSA multiplex fluorescent labeling we show that PSER129 positive punctate structures occur within inactive (i.e., cfos negative) T-box transcription factor 21 (TBX21) positive mitral cells and PSER129 within these cells was spatially associated with PK-resistant alpha-synuclein. Ubiquitin was found in PSER129 mitral cells but was not closely associated with PSER129. Biotinylation by antigen recognition (BAR) identified 125 PSER129-interacting proteins in the OB of healthy mice, which were significantly enriched for presynaptic vesicle trafficking/recycling, SNARE, fatty acid oxidation, oxidative phosphorylation, and RNA binding. TSA multiplex labeling confirmed the physical association of BAR identified protein Ywhag with PSER129 in the OB and in other regions across the neuroaxis. We conclude that PSER129 accumulates in mitral cells of the healthy OB as part of alpha-synuclein normal cellular functions. Incidental LP has been reported in the OB, and therefore we speculate that for synucleinopathies either; the disease processes begin locally in OB mitral cells or a systemic disease process is most apparent in the OB because the natural tendency to accumulate PSER129. Significance StatementMultiple lines of evidence have suggested that the disease process in some synucleinopathies begins in the olfactory bulb. Here we demonstrated that disease-associated phosphorylated alpha-synuclein preferentially occurs in mitral cells of the healthy mammalian olfactory bulb. We identified the protein interactome of phosphorylated alpha-synuclein in the healthy mouse olfactory bulb and established phosphorylated alpha-synuclein associates with presynaptic glutamatergic vesicles, SNARE machinery, and RNA metabolism machinery. Our data implicates olfactory bulb mitral cells in synucleinopathy pathogenesis. These findings advance our understanding of synucleinopathy disease origins and set the stage for new experimental models to interrogate the pathogenesis of synucleinopathies.

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bioRxiv2020

Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits

Epidemiological studies suggest a link between type-2 diabetes and Parkinsons disease (PD) risk. Treatment of type-2 diabetes with insulin sensitizing drugs lowers the risk of PD. We previously showed that the insulin sensitizing drug, MSDC-0160, ameliorates pathogenesis in some animal models of PD. MSDC-0160 reversibly binds the mitochondrial pyruvate carrier (MPC) protein complex, which has an anti-inflammatory effect and restores metabolic deficits. Since PD is characterized by the deposition of -synuclein (Syn), we hypothesized that inhibiting the MPC might directly inhibit Syn aggregation in vivo in mammals. To answer if modulation of MPC can reduce the development of Syn assemblies, and reduce neurodegeneration, we treated two chronic and progressive mouse models; a viral vector-based Syn overexpressing model and a pre-formed fibril (PFF) Syn seeding model with MSDC-0160. These two models present with distinct types of Syn pathology but lack inflammatory or autophagy deficits. Contrary to our hypothesis, we found that a modulation of MPC in these models did not reduce the accumulation Syn aggregates or mitigate neurotoxicity. Instead, MSDC-0160 changed the post-translational modification and aggregation features of the Syn. These results are consistent with the lack of a direct effect on MPC modulation on synuclein clearance in these models.

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bioRxiv2020

Gut microbiome dysbiosis is associated with elevated toxic bile acids in Parkinson's disease

The gut microbiome can impact brain health and is altered in Parkinsons disease (PD) patients. Here, we investigate changes in the functional microbiome in the appendix of PD patients relative to controls by metatranscriptomic analysis. We find microbial dysbiosis affecting lipid metabolism, particularly an upregulation of bacteria responsible for secondary bile acid synthesis. Proteomic and transcript analysis corroborates a disruption in cholesterol homeostasis and lipid catabolism. Bile acid analysis reveals an increase in microbially-derived, toxic secondary bile acids. Synucleinopathy in mice induces similar microbiome alterations to those of PD patients. The mouse model of synucleinopathy has elevated DCA and LCA. An analysis of blood markers shows evidence of biliary abnormalities early in PD, including elevated alkaline phosphatase and bilirubin. Increased bilirubin levels are also evident before PD diagnosis. In sum, microbially-derived toxic bile acids are heightened in PD and biliary changes may even precede the onset of overt motor symptoms.

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bioRxiv2020

Alterations in odor hedonics in the Tg6799 Alzheimer's disease mouse model and the influence of sex

Olfactory impairments, including deficits in odor detection, discrimination, recognition, and changes in odor hedonics are reported in the early stages of Alzheimers disease (AD). Rodent models of AD display deficits in odor learning, detection, and discrimination - recapitulating the clinical condition. However, the impact of familial AD genetic mutations on odor hedonics is unknown. We tested 2-, 4-, and 6-months old 5XFAD (Tg6799) mice in the five-port odor multiple-choice task designed to assay a variety of odor-guided behaviors, including odor preferences/hedonics. We found that 5XFAD mice investigated odors longer than controls, an effect that was driven by 6-months old mice. Interestingly, this effect was carried by females in the 5XFAD group, who investigated odors longer than age-matched males. Upon examining behavior directed towards individual odors to test for aberrant odor preferences, we uncovered that 5XFAD females at several ages displayed heightened preferences towards some of the odors, indicating aberrant hedonics. We observed no impairments in the ability to engage in the task in 5XFAD mice. Taken together, 5XFAD mice, particularly 5XFAD females, displayed prolonged odor investigation behavior and enhanced preferences to certain odors. The data provide insight into hedonic alterations which may occur in AD mouse models, and how these are influenced by biological sex.

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bioRxiv2020

Alpha-synuclein expression supports interferon stimulated gene expression in neurons

The protein alpha-synuclein (asyn) is predominantly expressed in neurons and is associated with neurodegenerative diseases like Parkinsons disease (PD); yet, a functional role for asyn in neurons is not clearly established. We have previously shown that asyn expression is up-regulated following viral infection in neurons and is critical for host immune responses to RNA virus infections. Here, we investigate the mechanisms underlying asyn-dependent immune responses to RNA virus infection in the brain. Using asyn knock-out (KO) mice and human neuronal models, we show that asyn is required for expression of the full repertoire of interferon-stimulated genes (ISGs) in neurons following acute RNA virus infection. Furthermore, treatment of asyn KO human neurons with poly I:C or type I interferon also fail to induce expression of the full complement of ISGs suggesting that asyn plays an important role in modulating neuronal innate immune responses. In brain tissue, asyn-dependent ISG expression is independent of microglia activation and supports activation of infiltrating lymphocytes following viral challenge. We also show that virus infections lead to accumulation of phosphorylated S129 asyn in human and non-human primate neuronal tissues. In a model of pS129 asyn pathology, we found that infection with West Nile virus increases microglia activation but does not significantly alter pS129 asyn pathology in the mouse model. Taken together, our results establish asyn as a novel, neuron-specific modulator of innate immunity by a mechanism that promotes interferon-stimulated gene expression and links responses to virus infection with formation of phosphorylated S129-asyn in neuronal tissue.

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bioRxiv2020

α-Synuclein perturbs in vivo neural activity following seeding in the olfactory bulb

BACKGROUNDParkinsons disease (PD) neuropathology is characterized by intraneuronal protein aggregates composed of misfolded -Synuclein (-Syn), as well as degeneration of substantia nigra dopamine neurons. Deficits in olfactory perception and aggregation of -Syn in the olfactory bulb (OB) are observed during early stages of PD, and have been associated with the PD prodrome, before onset of the classic motor deficits. -Syn fibrils injected into the OB of mice cause progressive propagation of -Syn pathology throughout the olfactory system and are coupled to olfactory perceptual deficits. OBJECTIVEWe hypothesized that accumulation of pathogenic -Syn in the OB impairs neural activity in the olfactory system. METHODSTo address this, we monitored spontaneous and odor-evoked local field potential dynamics in awake wild type mice simultaneously in the OB and piriform cortex (PCX) one, two, and three months following injection of pathogenic preformed -Syn fibrils in the OB. RESULTSWe detected -Syn pathology in both the OB and PCX. We also observed that -Syn fibril injections influenced odor-evoked activity in the OB. In particular, -Syn fibril-injected mice displayed aberrantly high odor-evoked power in the beta spectral range. A similar change in activity was not detected in the PCX, despite high levels of -Syn pathology. CONCLUSIONSTogether, this work provides evidence that synucleinopathy impacts in vivo neural activity in the olfactory system at the network-level.

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bioRxiv2020

Deficits in olfactory sensitivity in a mouse model of Parkinson's disease revealed by plethysmography of odor-evoked sniffing

Hyposmia is evident in over 90% of Parkinsons disease (PD) patients. A characteristic of PD is intraneuronal deposits composed in part of -synuclein fibrils. Based on the analysis of post-mortem PD patients, Braak and colleagues suggested that early in the disease -synuclein pathology is present in the dorsal motor nucleus of the vagus, as well as the olfactory bulb and the anterior olfactory nucleus, and then later affects other interconnected brain regions. Here, we bilaterally injected -synuclein preformed fibrils into the olfactory bulb of wild type male and female mice. Six-months after injection, the anterior olfactory nucleus and the piriform cortex displayed a high -synuclein pathology load. We evaluated olfactory perceptual function by monitoring odor-evoked sniffing behavior in a plethysmograph at one-, three- and six-months after injection of -synuclein fibrils. At all-time points, females injected with fibrils exhibited reduced odor detection sensitivity, which was detectable with the semi-automated plethysmography apparatus, but not a buried pellet test. In future studies, this sensitive methodology we used to assess olfactory detection deficits could be used to define how -synuclein pathology affects other aspects of olfactory perception in PD models and to clarify the neuropathological underpinnings of these deficits. Highlights- -synuclein pathology spreads through neuronally-connected areas after bilateral injection of preformed fibrils into the olfactory bulb. - A plethysmograph and an olfactometer were used for a semi-automated screen of odor-evoked sniffing as an assay for odor detection sensitivity. - Bilateral olfactory bulb injections of -synuclein preformed fibrils in female mice led to reduced sensitivity for detecting odors. - The semi-automated plethysmography apparatus was more sensitive at detecting odor detection deficits than the buried pellet test.

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bioRxiv2020

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

Background: -Synuclein (-syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of -synucleinopathies, such as Parkinsons 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 -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. Objective: To study the role of the adaptive immune system with respect to -syn pathology. Methods: We injected human -syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated -syn pathology, proteinase K-resistant -syn pathology and microgliosis in the striatum, substantia nigra and frontal cortex. We also assessed the impact of adoptive transfer of naive T and B cells into PFF-injected immunocompromised mice. Results: Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated -syn pathology in the substantia nigra. Reconstituting the T cell population decreased the accumulation of phosphorylated -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 -synucleinopathy.

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