Biology subjects

Prigent, A.

Publications and source records attributed to Prigent, A..

7 recordsLinked to original sources

bioRxiv2026

Rise-and-fall dynamics reveal a molecular and cellular vulnerability axis in prion-like α-synuclein propagation

The spread of misfolded proteins through neuronal circuits is a defining feature of neurodegenerative disease, yet the dynamics underlying this process remain poorly understood. Most studies rely on sparsely sampled datasets that capture spatial patterns of pathology but not their temporal evolution. Here, we analyze longitudinal histopathology measurements of -synuclein pathology across hundreds of brain regions in a mouse model of Parkinsons disease. Network-based dynamical modeling shows that regional pathology does not simply accumulate but instead follows rise-and-fall trajectories across the brain. The inferred parameter landscape reveals a one-dimensional vulnerability axis along which regions with stronger rise-and-fall dynamics have elevated energy metabolism and greater monoaminergic neuronal composition. This vulnerability axis replicates in an independent histopathological dataset, indicating that its dominant transcriptomic structure is preserved. Together, these results suggest that regional vulnerability collapses onto a low-dimensional molecular and cellular axis defined by rise-and-fall dynamics.

neuroscience↗

bioRxiv2025

Lewy pathology accumulates in swollen corticostriatal synapses in α-synucleinopathies

Lewy body diseases (LBD), including Parkinsons disease (PD), Parkinsons disease dementia (PDD), and dementia with Lewy bodies (DLB), are neurodegenerative disorders characterized by the accumulation of misfolded -synuclein in the form of Lewy pathology. A hallmark of these diseases is degeneration of the nigrostriatal pathway, resulting in loss of dopaminergic input to the striatum and consequent motor dysfunction. Lewy pathology is present in many regions outside the substantia nigra, and cortical Lewy pathology is the best correlate of cognitive decline in individuals that develop dementia. In addition, there is a high burden of neuritic Lewy pathology in the putamen, though the neuronal origin of this pathology is unclear. In the current study, we quantified the burden of Lewy pathology in the putamen across the spectrum of LBDs. Immunohistochemistry was used to quantify the Lewy burden in the putamen, cingulate and frontal cortices of 9 controls and 24 LBD cases. Even in PD cases without dementia, we observed a nearly complete striatal dopaminergic denervation among LBDs. Consistent with this denervation, most -synuclein pathology did not co-localize with dopaminergic terminals, but was instead enriched in excitatory, VGLUT1-positive terminals. This enrichment in glutamatergic terminals was associated with swollen axons, but not with overall loss of VGLUT1 terminals. These findings suggest that Lewy pathology accumulates at excitatory corticostriatal synapses prior to overt synaptic degeneration and could contribute to cognitive decline in LBDs.

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↗

bioRxiv2023

A topographical atlas of alpha-Synuclein dosage and cell-type expression in the mouse brain and periphery

Parkinsons disease (PD) is the second most common neurodegenerative disease worldwide and presents pathologically with Lewy pathology and dopaminergic neuron loss. Lewy pathology contains aggregated Synuclein (Syn), a protein encoded by the SNCA gene which is also mutated or duplicated in a subset of familial PD cases. Due to its predominant presynaptic localization, immunostaining for the protein results in diffuse signal, providing little insight into the types of cells expressing Syn. As a result, insight into Syn expression-driven cellular vulnerability has been difficult to ascertain. Using a combination of knock-in mice that target Syn to the nucleus of cells (SncaNLS) and in situ hybridization of Snca in wild-type mice, we systematically map the topography and cell types expressing Syn in the mouse brain, spinal cord, retina, and gut. We find a high degree of correlation between Syn protein and RNA levels across multiple brain regions and further identify cell types with low and high Syn. We found that Syn is highly expressed in neurons, particularly those involved in PD and to a lower extent in non-neuronal cell types, notably those of oligodendrocyte lineage. We also find that Syn is devoid in certain neuron types (e.g. ChAT-positive motor neurons), and that all enteric neurons express Syn to a certain degree. Taken together, this atlas provides much-needed insight into the cellular topography of Syn, and provides a quantitative map to test assumptions about the role of Syn in network vulnerability in PD and other Synucleinopathies.

neuroscience↗

bioRxiv2022

Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson's disease

Parkinsons disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by the accumulation of misfolded -synuclein in the form of Lewy pathology. While most cases are sporadic, there are rare genetic mutations that cause disease and more common variants that increase incidence of disease. The most prominent genetic mutations for PD and DLB are in the GBA1 and LRRK2 genes. GBA1 mutations are associated with decreased glucocerebrosidase activity and lysosomal accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Previous studies have shown a link between this enzyme and lipids even in sporadic PD. However, it is unclear how the protein pathologies of disease are related to enzyme activity and glycosphingolipid levels. To address this gap in knowledge, we examined quantitative protein pathology, glucocerebrosidase activity and lipid substrates in parallel from 4 regions of 91 brains with no neurological disease, idiopathic, GBA1-linked, or LRRK2-linked PD and DLB. We find that several biomarkers are altered with respect to mutation and disease severity. We found mild association of glucocerebrosidase activity with disease, but a strong association of glucosylsphingosine with -synuclein pathology, irrespective of genetic mutation. This association suggests that Lewy pathology precipitates changes in lipid levels related to disease severity.

neuroscience↗

bioRxiv2020

Tau accumulates in Crohn's disease gut

A sizeable body of evidence has recently emerged to suggest that gastrointestinal inflammation might be involved in the development of Parkinsons disease. There is now strong epidemiological and genetical evidence linking Parkinsons disease to inflammatory bowel diseases and we recently demonstrated that the neuronal protein alpha-synuclein, which is critically involved in Parkinsons disease pathophysiology, is upregulated in inflamed segments of Crohns colon. The microtubule associated protein tau is another neuronal protein critically involved in neurodegenerative disorders but, in contrast to alpha-synuclein, no data are available about its expression and phosphorylation patterns in inflammatory bowel diseases. Here, we examined the expression levels of tau isoforms, their phosphorylation profile and truncation in colon biopsy specimens from 16 Crohns disease and 6 ulcerative colitis patients and compared them to samples from 16 controls. Additional experiments were performed in full thickness segments of colon of 5 Crohns disease and 5 control subjects, in primary cultures of rat enteric neurons and in Nrf2 knockout mice. Our results show the upregulation of two main human tau isoforms in the enteric nervous system in Crohns disease but not in ulcerative colitis. This upregulation was not transcriptionally regulated but instead likely resulted from a decrease in protein clearance via an Nrf2 pathway. Our findings, which provide the first detailed characterization of tau in Crohns disease, suggest that the key proteins involved in neurodegenerative disorders such as alpha-synuclein and tau, might also play a role in Crohns disease.

neuroscience↗

bioRxiv2019

Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in non-human primates

AO_SCPLOWBSTRACTC_SCPLOWDopaminergic neuronal cell death, associated with intracellular -synuclein (-syn)-rich protein aggregates (termed Lewy bodies), is a well-established characteristic of Parkinsons disease. Much evidence, accumulated from multiple experimental models has suggested that -syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct -syn pathogenic structures derived from PD patients. Unexpectedly, our results show that, in non-human primates, a small amount of singular -syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD as multiple causes can induce similar outcome regarding dopaminergic neurodegeneration.

neuroscience↗