Biology subjects

Paulus, A.

Publications and source records attributed to Paulus, A..

5 recordsLinked to original sources

bioRxiv2025

Microplastic Exposure Promotes Amyloid Misfolding and Metabolic Impairment at Sub-Lethal Doses in an In Vitro Cellular Model of Alzheimer's Disease

Microplastics and nanoplastics (MNPs) are ubiquitous environmental pollutants with increasing implications for human health. While their presence in human tissues is established, the molecular mechanisms driving their potential neurotoxicity remain unclear. This study investigates the impact of polystyrene (PS) on amyloid protein misfolding and cellular metabolism using Optical Photothermal Infrared (O-PTIR) spectroscopy, a label-free, sub-diffraction imaging technique. Our results reveal that PS exposure promotes pathological protein misfolding, specifically increasing {beta}-sheet-rich conformations, and disrupts metabolic homeostasis at sub-lethal doses. These suggest that the microplastic surface acts as a catalytic scaffold for amyloid aggregation, driving cellular dysfunction prior to acute toxicity. This identifies a plausible molecular pathway by which environmental MNP pollution contributes to the risk and progression of neurodegenerative diseases, highlighting the need for risk assessments that look beyond simple cell survival.

biochemistry↗

bioRxiv2025

Galectin-3 deletion modulates microglial phenotype and Aβ response via TREM2 activation while attenuating neuroinflammation

Neuroinflammation is a hallmark of Alzheimers disease (AD), yet the molecular mediators driving microglial dysfunction and neurotoxicity remain poorly understood. Here, we identify Galectin-3 (Gal3) as a central regulator of plaque-associated microglial responses, linking amyloid-beta (A{beta}) aggregation, lysosomal function and plaque-associated neuritic damage. Using postmortem brain tissue from AD patients, we demonstrated that Gal3 microglia are selectively enriched around highly immunogenic dense-core plaques, and correlate with increased LAMP1+ dystrophic neurites. Notably, Gal3 was also detected in extra-microglial dystrophic structures and in close association with extracellular amyloid fibrils, suggesting a role in both intracellular and extracellular A{beta} dynamics. In APP mice, Gal3 deficiency resulted in more compact plaques, reduced neuronal dystrophies and increased TREM2 expression around amyloid plaques, suggesting altered plaque-associated microglial responses. Mechanistically, in vitro studies revealed that Gal3 modulates A{beta} uptake and its intracellular processing while lysosomal stress conditions showed increased A{beta} fibrillation from monomeric species in Gal3-deficient microglia. In parallel, cell-free assays demonstrated that Gal3 directly interacts with A{beta} and selectively inhibits secondary nucleation, thereby stabilizing intermediate assemblies associated with increased neurotoxic potential. Finally, in silico and transcriptomic analysis revealed that Gal3 interacts with key immune receptor patterns, having leucine-rich repeats as well as immunoglobulin-like domains. Moreover, Gal3 favors pro-inflammatory microglial programs, while its deletion suppresses type I interferon and microglial neurodegenerative (MGnD) signatures. Together, these findings position Gal3 as a central regulator of amyloid aggregation, lysosomal dysfunction, and microglial activation, driving a neurotoxic phase of AD and highlighting a potential therapeutic window for intervention. Significance StatementNeuroinflammation and amyloid-beta (A{beta}) plaques drive Alzheimers disease progression, but the molecular bridges between plaque formation, microglial dysfunction, and neurodegeneration remain unclear. This study identifies Galectin-3 (Gal3) as a pivotal regulator at this interface. We demonstrate that Gal3 is enriched around amyloid dense-core plaques in human brains and directly shapes A{beta} aggregation into highly neurotoxic intermediate structures. Genetic deletion of Gal3 in Alzheimers mouse models reduces nerve cell damage and change microglial cells toward a protective, less inflammatory state. By linking extracellular protein aggregation with intracellular lysosomal stress and inflammatory gene expression, these findings establish Gal3 as a major driver of Alzheimers neurotoxicity and highlight it as a promising therapeutic target

neuroscience↗

bioRxiv2023

Homologs of the plastidal preprotein translocase Tic20 mediate organelle assembly in bacteria

Organelle-specific protein translocation systems are essential for organelle biogenesis and maintenance in eukaryotes but thought to be absent from prokaryotic organelles. Here, we identified that MamF-like proteins involved in the formation of bacterial magnetosome organelles share an ancient origin with Tic20 protein translocases found in chloroplasts. Deletion of mamF-like genes in the alphaproteobacterium Magnetospirillum gryphiswaldense results in severe defects in organelle positioning, biomineralization, and magnetic navigation. Consistent with translocase-like functions, these defects are caused by the loss of magnetosome targeting of a subset of organellar proteins containing C-terminal glycine-rich integral membrane domains. Our findings suggest that organelle-specific protein translocation systems may indeed play a role in bacterial organelle formation.

microbiology↗

bioRxiv2021

SARS-CoV-2 variant evolution in the United States: High accumulation of viral mutations over time likely through serial Founder Events and mutational bursts.

Since the first case of COVID-19 in December 2019 in Wuhan, China, SARS-CoV-2 has spread worldwide and within a year has caused 2.29 million deaths globally. With dramatically increasing infection numbers, and the arrival of new variants with increased infectivity, tracking the evolution of its genome is crucial for effectively controlling the pandemic and informing vaccine platform development. Our study explores evolution of SARS-CoV-2 in a representative cohort of sequences covering the entire genome in the United States, through all of 2020 and early 2021. Strikingly, we detected many accumulating Single Nucleotide Variations (SNVs) encoding amino acid changes in the SARS-CoV-2 genome, with a pattern indicative of RNA editing enzymes as major mutators of SARS-CoV-2 genomes. We report three major variants through October of 2020. These revealed 14 key mutations that were found in various combinations among 14 distinct predominant signatures. These signatures likely represent evolutionary lineages of SARS-CoV-2 in the U.S. and reveal clues to its evolution such as a mutational burst in the summer of 2020 likely leading to a homegrown new variant, and a trend towards higher mutational load among viral isolates, but with occasional mutation loss. The last quartile of 2020 revealed a concerning accumulation of mostly novel low frequency replacement mutations in the Spike protein, and a hypermutable glutamine residue near the putative furin cleavage site. Finally, the end of the year data revealed the presence of known variants of concern including B.1.1.7, which has acquired additional Spike mutations. Overall, our results suggest that predominant viral sequences are dynamically evolving over time, with periods of mutational bursts and unabated mutation accumulation. This high level of existing variation, even at low frequencies and especially in the Spike-encoding region may be become problematic when superspreader events, akin to serial Founder Events in evolution, drive these rare mutations to prominence. AUTHOR SUMMARYThe pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused the death of more than 2.29 million people and continues to be a severe threat internationally. Although simple measures such as social distancing, periodic lockdowns and hygiene protocols were immediately put into force, the infection rates were only temporarily minimized. When infection rates exploded again new variants of the virus began to emerge. Our study focuses on a representative set of sequences from the United States throughout 2020 and early 2021. We show that the driving force behind the variants of public health concern, is widespread infection and superspreader events. In particular, we show accumulation of mutations over time with little loss from genetic drift, including in the Spike region, which could be problematic for vaccines and therapies. This lurking accumulated genetic variation may be a superspreader event from becoming more common and lead to variants that can escape the immune protection provided by the existing vaccines.

genetics↗

bioRxiv2018

Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease

Alzheimers disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (A{beta}) peptide, intraneuronal tau neurofibrillary tangles and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimers disease) mice, and found specifically expressed in microglia associated with A{beta} plaques. Single nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated to an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data demonstrated the requirement of gal3 to fully activate microglia in response to fibrillar A{beta}. Gal3 deletion decreased the A{beta} burden in 5xFAD mice and improved cognitive behavior. Electron microscopy of gal3 in AD mice demonstrated i) a preferential expression of gal3 by plaque-associated microglia, ii) its presence in the extracellular space and iii) its association to A{beta} plaques. Low concentrations (1 nM) of pure gal3 promoted cross-seeding fibrilization of pure A{beta}. Importantly, a single intrahippocampal injection of gal3 along with A{beta} monomers in WT mice was sufficient to induce the formation of insoluble A{beta} aggregates that were absent when gal3 was lacking. High-resolution microscopy (STORM) demonstrated close co-localization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 CRD domain. Furthermore, gal3 stimulated the TREM2-DAP12 signaling pathway. In conclusion, we provide evidence that gal3 is a central regulator of microglial immune response in AD. It drives proinflammatory activation and A{beta} aggregation, as well as acting as an endogenous ligand to TREM2, a key receptor driving microglial response under disease conditions. Gal3 inhibition may, hence, be a potential pharmacological approach to counteract AD.

neuroscience↗