Biology subjects

Berg, T.

Publications and source records attributed to Berg, T..

5 recordsLinked to original sources

bioRxiv2026

Extracellular protein catabolism drives regulated nitrogen handling and ammonia buffering in acute myeloid leukemia

Acute myeloid leukemia (AML) cells exhibit pronounced metabolic plasticity, yet how amino acid supply is coordinated to sustain leukemic metabolism remains poorly understood. Here, we show that AML cells catabolize extracellular proteins as a major source of amino acids through lysosomal degradation of albumin. This proteocatabolic activity supports anabolic processes and mitochondrial energy production and establishes a regulated, high-throughput regime of primary nitrogen-containing metabolites (nitrogen regimen). Sustained proteocatabolism inevitably generates ammonia, and we find elevated ammonia concentrations in bone marrow plasma from newly diagnosed AML patients that decline with effective induction therapy. Using metabolomics, isotope tracing and targeted genetic and pharmacological manipulations, we identify glutamate-ammonia ligase (GS/GLUL) as a central enzyme that buffers proteocatabolism-derived ammonia by stabilizing intracellular nitrogen homeostasis. Loss of GS function limits sustainable nitrogen handling capacity, thereby impairing leukemic proliferation and delaying disease progression in vivo. Together, our findings define extracellular protein catabolism as a regulating nitrogen management strategy in AML and reveal GS as a capacity-defining vulnerability of proteocatabolic growth.

cancer biology↗

bioRxiv2024

Alzheimer's disease induced neurons bearing PSEN1 mutations exhibit reduced excitability

Alzheimers disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in PSEN1 (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between PSEN1 mutations and neuronal excitability remains to be fully elucidated. This study examined induced pluripotent stem cell (iPSC)-derived NGN2 induced neurons (iNs) from fAD patients with PSEN1 mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both PSEN1 mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of PSEN1 mutations on neuronal excitability. Additionally, both PSEN1 backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding the disease pathogenesis.

cell biology↗

bioRxiv2022

No need for extensive artifact rejection for ICA - A multi-study evaluation on stationary and mobile EEG datasets

ObjectiveElectroencephalography (EEG) studies increasingly make use of more ecologically valid experimental protocols involving mobile participants who actively engage with their environment (MoBI; Gramann et al., 2011). These mobile paradigms lead to increased artifacts in the recorded data that are often treated using Independent Component Analysis (ICA). When analyzing EEG data, especially in a mobile context, removing samples regarded as artifactual is a common approach before computing ICA. Automatic tools for this exist, such as the automatic sample rejection of the AMICA algorithm (Palmer et al., 2011), but the impact of the two factors movement intensity and the automatic sample rejection has not been systematically evaluated yet. ApproachWe computed AMICA decompositions on eight datasets from six open-access studies with varying degrees of movement intensities using increasingly conservative sample rejection criteria. We evaluated the subsequent decomposition quality in terms of the component mutual information, the amount of brain, muscle, and "other" components, the residual variance of the brain components, and an exemplary signal-to-noise ratio. Main resultsWe found that increasing movements of participants led to decreasing decomposition quality for individual datasets but not as a general trend across all movement intensities. The cleaning strength had less impact on decomposition results than anticipated, and moderate cleaning of the data resulted in the best decompositions. SignificanceOur results indicate that the AMICA algorithm is very robust even with limited data cleaning. Moderate amounts of cleaning such as 5 to 10 iterations of the AMICA sample rejection with 3 standard deviations as the threshold will likely improve the decomposition of most datasets, irrespective of the movement intensity.

neuroscience↗

bioRxiv2020

Identification of repurposable cytoprotective drugs for Vanishing White Matter Disease

Vanishing white matter disease (VWMD) is a rare leukodystrophy involving loss of function mutations of the guanine exchange factor eIF2B and typically presenting with juvenile onset. We aimed to identify repurposable FDA approved drugs in an in vitro drug screen using patient-derived fibroblasts and induced pluripotent stem cell (iPSC)-derived astrocytes. Dysregulated GADD34 and CHOP were identified in patient fibroblasts and iPSC-derived astrocytes under proteasomal stress conditions. A drug screen from a 2400 FDA approved drug library with EIF2B5 disease patient fibroblasts identified 113 anti-inflammatory drugs as a major class of hits with cytoprotective effects. A panel of potential candidate drugs including berberine, deflazacort, ursodiol, zileuton, guanabenz and Anavex 2-73, and preclinical ISRIB, increased cell survival of MG132-stressed EIF2B2 and EIF2B5 disease VWMD astrocytes, and were further investigated for their effect on the integrated stress response and mitochondrial stress. ISRIB but not other drugs significantly affected eIF2 phosphorylation and GADD34 expression. Ursodiol demonstrated capacity to reduce complex I subunit upregulation, ameliorate oxidative stress, loss of mitochondrial membrane potential and upregulation of eIF2B subunits in VWMD astrocytes, highlighting its potential as a cytoprotective compound for VWMD.

neuroscience↗

bioRxiv2020

Neurodegenerative disease-associated protein aggregates are poor inducers of the heat shock response in neuronal-like cells

Protein aggregation that results in the formation of inclusions is strongly correlated with neuronal death and is a pathological hallmark common to many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntingtons disease. Cells are thought to dramatically up-regulate the levels of heat shock proteins during periods of cellular stress via induction of the heat shock response (HSR). Heat shock proteins are well-characterised molecular chaperones that interact with aggregation-prone proteins to either stabilise, refold, or traffic protein for degradation. The reason why heat shock proteins are unable to maintain the solubility of particular proteins in neurodegenerative disease is unknown. We sought to determine whether neurodegenerative disease-associated protein aggregates can induce the HSR. Here, we generated a neuroblastoma cell line that expresses a fluorescent reporter under conditions of HSR induction, for example heat shock. Using these cells, we show that the HSR is not induced by exogenous treatment with aggregated forms of Parkinsons disease-associated -synuclein or the ALS-associated G93A mutant of superoxide dismutase-1 (SOD1G93A). Furthermore, flow cytometric analysis revealed that intracellular expression of SOD1G93A or a pathogenic form of polyQ-expanded huntingtin (Htt72Q), similarly, results in no or low induction of the HSR. In contrast, expression of a non-pathogenic but aggregation-prone form of firefly luciferase (Fluc) did induce an HSR in a significantly greater proportion of cells. Finally, we show that HSR induction is dependent on the intracellular levels of the aggregation-prone proteins, but the pathogenic proteins (SOD1G93A and Htt72Q) elicit a significantly lower HSR compared to the non-pathogenic proteins (Fluc). These results suggest that pathogenic proteins either evade detection or impair induction of the HSR in neuronal-like cells. Therefore, defective HSR induction may facilitate the initiation of protein aggregation leading to inclusion formation in neurodegenerative diseases.

cell biology↗