Biology subjects

Meyerdirk, L.

Publications and source records attributed to Meyerdirk, L..

10 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.

neuroscience↗

bioRxiv2025

Helicobacter pylori infection and α-synuclein pathology drive parallel neurodegenerative pathways in the substantia nigra

Parkinsons disease is a common neurodegenerative disease related to both genetic and environmental insults. Epidemiological studies have linked Helicobacter pylori (H. pylori) infection to Parkinsons disease risk, but the underlying mechanisms of this association remain unclear. In this study, we investigate whether chronic infection with a pathogenic H. pylori strain can induce -synuclein aggregation or neurodegeneration, and whether infection clearance mitigates these effects. We also assessed whether H. pylori infection exacerbates -synuclein pathology and neuron loss when combined with seeding of -synuclein pathology. We find that chronic H. pylori infection induces a sustained immune response in the gut and plasma that leads to mild brain inflammation and dopaminergic neuron loss, independent of -synuclein pathology. These effects are attenuated by eradication of the infection. In mice with -synuclein pathology induced by pre-formed fibrils, H. pylori did not further exacerbate the extent of pathology or neuronal death. Together, these results suggest that H. pylori infection can lead to neurodegeneration through inflammatory mechanisms independent of -synuclein aggregation. Our findings offer mechanistic insights into how pathogens influence the risk and progression of Parkinsons disease.

neuroscience↗

bioRxiv2025

Seed structure and phosphorylation in the fuzzy coat impact tau seeding competency

Tau is a pathogenic protein in Alzheimers (AD) and other neurodegenerative diseases. The misfolding of tau into {beta}-sheet rich elongated filaments is thought to be a key event in disease pathogenesis, followed by subsequent templated recruitment of monomeric tau into this pathogenic form. Cryo-electron microscopy has revealed that specific tau conformations characterize different diseases. In this study, we explored how tau filament core structure and post-translational modifications in its disordered fuzzy coat influence its seeding capacity in primary neurons and mice. We show that the structure of the seeds affects seeding capacity, but that the AD tau core structure alone is insufficient to capture the full seeding capacity of AD tau. Proteolytic cleavage of AD tau which removes the fuzzy coat causes a loss in seeding capacity, as does removal of phosphorylation from the fuzzy coat by phosphatase treatment. Re-phosphorylation of phosphatase-treated AD tau by kinase treatment partially restores seeding activity. Finally, we find that filaments of recombinant tau with twelve phospho-mimetic residues (PAD12 tau) with the AD fold are able to recapitulate the seeding capacity of AD tau. Combined, these results suggest that the structure of the ordered core, together with phosphorylation in the fuzzy coat, confers the seeding capacity of tau filaments.

neuroscience↗

bioRxiv2024

Network analysis of α-synuclein pathology progression reveals p21-activated kinases as regulators of vulnerability

-Synuclein misfolding and progressive accumulation drive a pathogenic process in Parkinson's disease, yet many brain regions develop more or less pathology than would be predicted by connectivity alone, indicating that intrinsic biological factors influence regional vulnerability. Here, we combined whole brain mapping of -synuclein pathology in wildtype mice 3 days to 9 months after seeding with network diffusion modeling based on anatomical connectivity to derive quantitative measures of regional vulnerability. To identify molecular drivers of this vulnerability, we generated a brain-wide sPAtial Neuron Gene Expression Atlas (PANGEA) and compared regional transcriptional profiles with model-derived vulnerability scores. Vulnerable regions were enriched for specific cellular programs. Specific kinases were also enriched in vulnerable regions, leading to the identification of group II p21-activated kinases (PAKs) as candidate regulators of -synucleinopathy. Pharmacological inhibition of group II PAKs reduced -synuclein aggregation and protected against neuron loss in primary neurons, remained effective when administered after pathology initiation, and suppressed pathology in vivo. Consistent with these findings, genetic depletion of PAK5/6 also suppressed -synuclein aggregation. Together, these results establish a framework linking network-level measures to cellular mechanisms of selective vulnerability and nominate group II PAKs as promising disease-modifying therapeutic targets for Parkinson's disease.

neuroscience↗

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.

neuroscience↗

bioRxiv2023

Spatial transcriptomics reveals molecular dysfunction associated with Lewy pathology

Lewy pathology composed of -synuclein is the key pathological hallmark of Parkinsons disease (PD), found both in dopaminergic neurons that control motor function, and throughout cortical regions that control cognitive function. Recent work has investigated which dopaminergic neurons are most susceptible to death, but little is known about which neurons are vulnerable to developing Lewy pathology and what molecular changes an aggregate induces. In the current study, we use spatial transcriptomics to selectively capture whole transcriptome signatures from cortical neurons with Lewy pathology compared to those without pathology in the same brains. We find, both in PD and in a mouse model of PD, that there are specific classes of excitatory neurons that are vulnerable to developing Lewy pathology in the cortex. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. This gene signature indicates that neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. However, beyond DNA repair gene upregulation, we find that neurons also activate apoptotic pathways, suggesting that if DNA repair fails, neurons undergo programmed cell death. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and identify a conserved signature of molecular dysfunction in both mice and humans.

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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.

neuroscience↗

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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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.

neuroscience↗

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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