Biology subjects

Kraemer, B.

Publications and source records attributed to Kraemer, B..

10 recordsLinked to original sources

bioRxiv2026

TMEM106B C-Terminal fragment aggregation exacerbates α-synuclein and TDP-43 proteinopathy phenotypes.

Genetic variation in the human gene encoding the lysosomal transmembrane protein 106B (TMEM106B) drives risk of neurodegenerative dementia. A C-terminal fragment of TMEM106B (TMEM CT) accumulates in lesions across neurodegenerative disease, potentially contributing to neurotoxicity and hampering efficacy of therapeutic interventions. Previously, we developed the first transgenic organism model of TMEM CT neuronal aggregation in Caenorhabditis elegans (C. elegans). We demonstrated that TMEM CT neuronal aggregation drives severe neuronal dysfunction and neuronal loss. To investigate the potential synergistic interaction of TMEM CT aggregation with other types of aggregated neurotoxic proteinopathies occurring in dementia, we assessed neuronal degeneration and pathogenic protein accumulation in bigenic C. elegans expressing TMEM CT and other key proteinopathies of neurodegeneration including a-synuclein, tau, and TAR DNA binding protein 43 (TDP-43). Our results showed strong neurotoxic synergy of TMEM106B with TDP-43 or -synuclein. However, we detected only mild synergy between TMEM106B and tau. This work provides evidence in support of TMEM CT aggregation as a significant participant in the neurodegenerative process attributed to other toxic protein aggregates. The work also highlights the importance of considering secondary proteinopathy contributions including TMEM CT aggregation when developing interventions against primary TDP-43 or -synuclein proteinopathies.

neuroscience↗

bioRxiv2026

Epigenetic control of S100A8/A9-driven monocytic inflammation licenses anti-leukemic functionality of immature NK cells during hematopoietic stem cell differentiation.

Inflammation is a key driver of hematopoietic dysfunction in myeloid malignancies, but its role in the context of hypomethylating therapy remains incompletely understood. Although 5-Azacytidine is used posttransplant in high-risk myelodysplastic syndrome (MDS), only 50% of patients show a clinical response. We provide evidence that inherent inflammatory properties of healthy donor CD34+ stem cells exist that are likely to contribute to the "response" seen in MDS patients. These are linked to epigenetic priming of the myeloid niche, resulting in S100A8/A9-driven inflammatory program that promotes functionality of immature NK cells. Using in vitro differentiation systems, multi-omic profiling, and a S100A9-/- mouse model, we find that 5-AzaC modulates inflammatory transcriptional programs through epigenetic rewiring of upstream regulatory elements. Loss of S100A9 disrupts myeloid differentiation, impairs NK cell maturation, and alters key developmental regulators including CEBPB, JUN, and NFIL3. In vivo, 5-AzaC restores these defects and primes NK cells in a time- and context-dependent manner. Re-analysis of the published Australian MDS/CMML cohort shows that "responders" display increased S100A8/A9 expression together with enhanced IFN-{gamma}, IL6-JAK-STAT3, and TNF signaling. These findings suggest that inflammatory myeloid programs may serve as predictive biomarkers and therapeutic targets to enhance NK cell-mediated graft-versus-leukemia activity posttransplant. SummaryO_LIWe provide compelling evidence that inherent properties of healthy donor CD34+ hematopoietic stem cells (SCs) exist that are likely to contribute to the "response" seen upon pre-emptive posttransplant 5-AzaC therapy of patients with high-risk myelodysplastic syndrome (MDS). C_LIO_LIThese properties are linked to a distinct form of epigenetic plasticity at upstream-located transcription factor (TF) binding sites. This may indirectly contribute to acute S100A8/A9-driven inflammation, which is demonstrable in distinct monocyte subsets and, importantly, also in NK cells thereby determining the characteristics of inflammatory monocyte-NK cell crosstalk. C_LIO_LIMice with a targeted deletion of S100A9 fail to upregulate CEBPB / JUN and NFIL3 which results in impaired myeloid priming and dysfunctional NK cell maturation, respectively. C_LIO_LIRe-analysis of the Australian MDS/CMML cohort confirms that MDS patients that "respond" to 5-AzaC exhibit activated IFN-{gamma}, IL6-JAK-STAT3, and TNF-signaling pathways in the context of upregulated S100A8/A9 after six months of treatment. C_LIO_LIOur study indicates that screening of healthy donors SCs for specific inflammatory markers in early developing monocytes could be used as a marker to predict which donor will have the potential of generating a S100A8/A9-driven inflammatory response. This may help identify patients with MDS as well as AML who are likely to benefit from low-dose, short-term 5-AzaC therapy as early as day 7 after transplantation, potentially resulting in increased graft-versus-leukemia (GvL) activity. C_LI

immunology↗

bioRxiv2025

Historical remote sensing highlights long-term persistence of Emperor Penguin (Aptenodytes forsteri) colonies

Historical remote sensing imagery, including digital Landsat and analog Keyhole have potential to inform Antarctic conservation by providing insights into habitat and population dynamics. A case in point is that their long temporal range, extending as far back as the 1960s, offers an unparalleled look into the distribution of Emperor Penguin (Aptenodytes forsteri) colonies and their habitat. Here we demonstrate that Keyhole and Landsat sensors are capable of detecting presence and long-term change in penguin guano on sea-ice despite challenging environmental conditions. For 18 of the 66 known emperor penguin colonies, we confirmed their presence in images that predate earliest published records. We further used dense time series from 1960s to 2024 of the Cape Washington colony to exemplify change in guano area over time - but found little variation in guano area. We show that the guano area undergoes two distinct stages during a breeding season (a stable and clustered early stage, and a diffused and widespread late stage). We correlated guano area with penguin colony size and found that guano area correlates with colony size (Spearmans {rho} = 0.59, p-value = 0.017). Taken together, our results suggest long term resilience of penguin colonies in face of global change, and highlight that the use of historical remote sensing imagery across the Antarctic can inform conservation efforts and benefit the ongoing historical studies of penguin colony dynamics. We highlight the benefit of remote sensing for documenting otherwise inaccessible colonies and for quantifying and understanding historical colony dynamics.

ecology↗

bioRxiv2025

Marker-independent imaging reveals a correlation of fibrotic and epigenetic alterations in endometriosis

IntroductionEndometriosis describes the presence of endometrial glands outside of the uterus and can cause various symptoms such as chronic pelvic pain, hypermenorrhea and infertility. These complications pose an extreme burden on the patients, especially as up to date, the average time until diagnosis can consume several years and requires invasive laparoscopy. ObjectivesThe aim of this study is to molecularly characterize endometrium and endometriosis using marker-independent Raman microspectroscopy to identify potential biomarkers and validate its diagnostic potential. MethodsAfter histopathological characterization of tissue sections of human endometrium and endometriosis, Raman microspectroscopy was performed on the gland region. Multivariate analysis of the hyperspectral maps was used to localize major subcellular structures and further decipher their molecular composition. Samples from different anatomical regions and throughout all menstrual cycle phases were analyzed. ResultsRaman imaging enabled label-free visualization of tissue morphology and submolecular tissue characterization. Distinct differences between endometrium and endometriosis were found for collagen type I and nuclear signatures. Spectral deconvolution allowed identification of a Raman biomarker indicative of fibrotic changes in endometriosis samples. Additionally, a significant increase in epigenetic 5mC foci and an increased signal intensity relevant for methylations was detected in nuclei of endometriosis. Furthermore, a neural network-based classification of Raman data resulted in high accuracies in discriminating endometrial and peritoneal tissue from endometriosis. ConclusionThe non-destructive approach by hyperspectral Raman imaging enabled for molecular sensitive characterization of endometriotic lesions which could not only be an asset in complementing histopathological tissue evaluation but combined with data-driven classification models support in situ tissue diagnosis.

biophysics↗

bioRxiv2025

Lifestyle, Early-life, and Genetic Health Risk Factors Underlying the Brain Age Gap: A Mega-Analysis Across 3,934 Individuals from the ENIGMA MDD Consortium

BackgroundLarge-scale studies show that adults with major depressive disorder (MDD) generally have a higher imaging-predicted age relative to their chronological age (i.e., positive brain age gap) compared to controls, though considerable within-group variation exists. This study examines lifestyle, early-life, and genetic health risk factors contributing to the brain age gap. Identifying risk and resilience factors could help protect brain and mental health. MethodsUsing an established model trained on FreeSurfer-derived brain regions (www.photon-ai.com/enigma_brainage), we generated brain age predictions for 1,846 controls and 2,088 individuals with MDD (aged 18-75) from 12 international cohorts. Polygenic risk scores (PRS) were calculated for major depression, C-reactive protein, and body mass index (BMI) using large-scale GWAS results. Linear mixed models were applied to assess lifestyle (BMI, smoking, education), early-life childhood trauma, and genetic (PRS) health risk associations with the brain age gap. Additionally, we evaluated the link between the brain age gap and peripheral biological age indicators (epigenetic clocks). ResultsHigher brain age gaps were significantly associated with BMI ({beta}=0.01, PFDR=0.02) and smoking ({beta}=0.11, PFDR=0.02), while lower brain age gaps were linked to higher education ({beta}=-0.02, PFDR=0.02). Higher childhood trauma scores predicted a higher brain age gap ({beta}=0.04, P=0.01). Higher brain age gaps were positively associated with all PRS ({beta}s=0.04-0.16, PsFDR=0.02-0.03). There were no significant interactions between diagnosis and assessed factors on the brain age gap. In a multivariable model, only modifiable health factors--BMI, smoking, and education--remained uniquely associated with brain age gaps. ConclusionsGenetic liability for depression and related traits is linked to poorer brain health, but health behaviors potentially offer a key opportunity for intervention. This study underscores the importance of targeting modifiable lifestyle factors to mitigate poor brain health in depressed individuals, an approach perhaps under-recognized in clinical practice.

neuroscience↗

bioRxiv2025

Investigation of the Role of the LC3 Conjugation System in Autophagy for Human Reward System Reactivity

ObjectivesThe dopaminergic reward system is involved in the etiology of psychiatric disorders, and autophagy has been suggested to interfere with dopamine release. LC3 conjugation plays a key role in autophagy and comprises modification of autophagy protein LC3 with phosphatidylethanolamine. We investigated whether LC3 conjugation may impact on the strength of activation in key regions of the mesolimbic reward system. MethodsTo test our hypothesis, responses of the reward system to conditioned stimuli were assessed using the desire-reason dilemma(DRD) paradigm, that allows for investigation of reward processing during fMRI. Association of a set of missense variants with reward system responses was analyzed in a sample of 214 participants. ResultsAs a main finding, the gene set was associated with both ventral tegmental area (VTA) and nucleus accumbens (NAc) responses to conditioned reward stimuli (empirical P-value R-VTA: 0.008, R-NAc: 0.009). Strongest missense variants were MAP1LC3B_rs113610787 (P=3.219e-05) for association with response in the L-NAc, and ATG4B_rs143448469 (P=4.366e-05) for the R-NAc. ConclusionsFindings provide evidence that variation of the LC3 conjugation system influences responses of the VTA and NAc to conditioned reward stimuli. Further studies are required to replicate the findings, and to investigate the possible role of LC3 conjugation in psychiatric disorders.

genetics↗

bioRxiv2024

Probing tau citrullination in Alzheimer's disease brains and mouse models of tauopathy

Tauopathies, which include Alzheimers disease (AD) share a common defining factor, namely misfolded tau protein. However, the "upstream" etiology and downstream clinical manifestations of tauopathies are quite diverse. Tau deposition elicits different pathological phenotypes and outcomes depending on the tau strain and regional susceptibility. Posttranslational modifications (PTM) can alter tau structure, function, networks, and its pathological sequalae. We uncovered a novel PTM of tau, named citrullination, caused by peptidyl arginine deiminase (PAD) enzymes. PAD induced citrullination irreversibly converts arginine residues to citrulline, producing net loss of positive charge, elimination of pi-pi interactions, and increased hydrophobicity. We observed increased PAD2 and PAD4 in Alzheimers disease (AD) brain and that they both can citrullinate tau. Tau can become citrullinated by PADs at all 14 arginine residues throughout the N-terminal domain (N-term), proline-rich domain (PR), microtubule binding repeat domain (MBR), and C-terminal domain (C-term) on full length tau (2N4R). Citrullination of tau impacts fibrillization and oligomerization rates in aggregation assays. Utilizing a panel of novel citrullinated tau (citR tau) antibodies, we identified citrullination of tau in vitro, several animal models of tauopathies, and Alzheimers disease (AD). CitR tau increased with Braak stage and was enriched in AD brains with higher phospho-tau burden. This work provides a new area of tau biology that signifies further consideration in the emerging spectrum of tauopathies and its clinical understanding.

neuroscience↗

bioRxiv2024

TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy.

Genetic variation in the lysosomal and transmembrane protein 106B (TMEM106B) modifies risk for a diverse range of neurodegenerative disorders, especially frontotemporal lobar degeneration (FTLD) with progranulin (PGRN) haplo-insufficiency, although the molecular mechanisms involved are not yet understood. Through advances in cryo-electron microscopy (cryo-EM), homotypic aggregates of the C-Terminal domain of TMEM106B (TMEM CT) were discovered as a previously unidentified cytosolic proteinopathy in the brains of FTLD, Alzheimers disease, progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB) patients. While it remains unknown what role TMEM CT aggregation plays in neuronal loss, its presence across a range of aging related dementia disorders indicates involvement in multi-proteinopathy driven neurodegeneration. To determine the TMEM CT aggregation propensity and neurodegenerative potential, we characterized a novel transgenic C. elegans model expressing the human TMEM CT fragment constituting the fibrillar core seen in FTLD cases. We found that pan-neuronal expression of human TMEM CT in C. elegans causes neuronal dysfunction as evidenced by behavioral analysis. Cytosolic aggregation of TMEM CT proteins accompanied the behavioral dysfunction driving neurodegeneration, as illustrated by loss of GABAergic neurons. To investigate the molecular mechanisms driving TMEM106B proteinopathy, we explored the impact of PGRN loss on the neurodegenerative effect of TMEM CT expression. To this end, we generated TMEM CT expressing C. elegans with loss of pgrn-1, the C. elegans ortholog of human PGRN. Neither full nor partial loss of pgrn-1 altered the motor phenotype of our TMEM CT model suggesting TMEM CT aggregation occurs downstream of PGRN loss of function. We also tested the ability of genetic suppressors of tauopathy to rescue TMEM CT pathology. We found that genetic knockout of spop-1, sut-2, and sut-6 resulted in weak to no rescue of proteinopathy phenotypes, indicating that the mechanistic drivers of TMEM106B proteinopathy may be distinct from tauopathy. Taken together, our data demonstrate that TMEM CT aggregation can kill neurons. Further, expression of TMEM CT in C. elegans neurons provides a useful model for the functional characterization of TMEM106B proteinopathy in neurodegenerative disease.

neuroscience↗

bioRxiv2023

Gene Set-Based Analysis of the Endosomal Sorting Processes Cargo Selection and Membrane Tubulation with Human Reward System Reactivity

Dysfunction of the dopaminergic reward system has been implicated in the pathophysiology of several neuropsychiatric disorders. The endosomal network encompasses important processes related to neurotransmission in dopamine neurons, e.g, endocytosis, sorting, recycling and degradation of receptors. In the present study, we investigated whether genetic variation influencing the endosomal sorting machinery, in particular cargo selection and membrane tubulation, may impact on the activation strength in key regions of the mesolimbic reward system, i.e. the ventral tegmental area (VTA) and the nucleus accumbens (NAc). To test our hypothesis, the VTA and NAc responses to conditioned reward stimuli were investigated using the desire-reason dilemma (DRD) paradigm during functional magnetic resonance imaging (fMRI). Association of these neural responses with a set of genetic variants related to endosomal sorting processes were tested in two independent samples (N = 182; N = 214). In the first sample, the gene set was associated with both VTA and NAc responses to conditioned reward stimuli [empirical P -values: R-VTA 0.0036; R-NAc 0.0016; L-NAc 0.0094], while the effect in the R-VTA could be replicated in the second sample [empirical P -value: R-VTA 0.0443] at the level of the gene set. For the NAc, an additional exploratory analysis of a patient-only subsample of the first sample (N = 64) suggested that the gene set may express its effect in this brain region predominantly in patients. These findings provide first evidence that the endosomal sorting processes cargo selection and membrane tubulation influence neural responses of the reward system to conditioned stimuli. Further studies are required to clarify the role of endosomal sorting processes in the pathophysiology of neuropsychiatric disorders.

genetics↗

bioRxiv2022

DNAJC13 influences responses of the extended reward system to conditioned stimuli: a genome-wide association study

Reward system dysfunction is implicated in the pathogenesis of major psychiatric disorders. We conducted a genome-wide association study (GWAS) to identify genes that influence activation strength of brain regions within the extended reward system in humans. A large homogeneous sample of 214 participants was genotyped and underwent functional magnetic resonance imaging (fMRI). All subjects performed the desire-reason dilemma (DRD) paradigm allowing systematic investigation of systems-level mechanisms of reward processing in humans. As a main finding, we identified the single nucleotide variant rs113408797 in the DnaJ Heat Shock Protein Family Member C13 gene (DNAJC13, alias RME-8), that strongly influenced the activation of the ventral tegmental area (VTA; p = 2.50E-07) and the nucleus accumbens (NAcc; p = 5.31E-05) in response to conditioned reward stimuli. Moreover, haplotype analysis assessing the information across the entire DNAJC13 locus demonstrated an impact of a five-marker haplotype on VTA activation (p = 3.21E-07), which further corroborates a link between this gene and reward processing. The present findings provide first direct empirical evidence that genetic variation of DNAJC13 influences neural responses within the extended reward system to conditioned stimuli. Further studies are required to investigate the role of this gene in the pathogenesis and pathophysiology of neuropsychiatric disorders.

genomics↗