Biology subjects

Pless, O.

Publications and source records attributed to Pless, O..

5 recordsLinked to original sources

bioRxiv2025

CBM KG: A Comorbidity-Centric Knowledge Graph Uncovering Causal Pathomechanisms Between COVID-19 and Neurodegenerative Diseases

SummaryCOVID-19 is increasingly recognized as a potential trigger or accelerator of neurodegenerative diseases such as Alzheimers and Parkinsons. To systematically explore the putative molecular and clinical associations between them, we present CBM KG (Causal Biological Mechanisms Knowledge Graph)--a manually curated, comorbidity-centric resource developed within the EU-funded COMMUTE project. CBM KG integrates over 2,800 cause-and-effect or correlative relationships from 63 peer-reviewed publications, highlighting key mechanisms such as viral entry routes, blood-brain barrier alteration, microglial activation, neuroinflammation, and APOE {varepsilon}4-associated susceptibility. Each relationship in the graph is fully traceable to its source evidence, ensuring transparency and reproducibility. Unlike general-purpose or single disease-focused knowledge graphs, CBM KG is specifically designed to represent causal biological mechanisms spanning both infectious and neurodegenerative processes. By encoding directional, cause-and-effect relationships, it supports the interpretation of clinical co-occurrences through plausible mechanistic links between overlapping disease pathways, offering high-resolution insights at both molecular and clinical levels. Availability and implementationThe BEL files, Neo4j database, and Cytoscape visualization files are publicly available at: https://github.com/SCAI-BIO/CBM-Comorbidity-KG.

bioinformatics↗

bioRxiv2025

Optimization and evaluation of complementary degrader discovery assays for application in screening

Targeted protein degradation (TPD) mediated by molecular glues is an innovative pharmaceutical paradigm. By binding to and modulating the surface of an E3-ligase component, molecular glue degraders can facilitate the recruitment of a specific target protein (or vice versa) and, ultimately, invoke target degradation. This mode of action results in specific challenges for the development of rational discovery strategies, and complex hit validation workflows may be required to reliably eliminate compounds that elicit non-specific effects. With the aim to guide screening efforts, we optimized two orthogonal cell-based, target-centric assays for degrader discovery: (1) a time-resolved FRET assay directly quantifying levels of target protein and its degradation (signal inhibition), and (2) an assay coupling TPD to cell growth (signal rescue). To enable a deeper understanding of the individual assays strengths and limitations, we compared their statistical performance as well as respective hit populations by screening a specifically designed collection of about 1000 compounds containing well annotated reference compounds and known frequent hitters. We found that the signal rescue format reliably and specifically captured active target degraders while it efficiently filtered out interfering or frequent hitter compounds. Importantly, this format achieved to retrieve lower potency hits, which might be desirable in order to confidently include as many diverse chemical starting points as possible at the start of a drug discovery project.

pharmacology and toxicology↗

bioRxiv2024

Morphological profiling in human dopaminergic neurons identifies mitochondrial uncoupling as a neuroprotective effect

Parkinsons disease (PD) involves multiple pathological processes in midbrain dopaminergic (mDA) neurons, including protein degradation defects, vesicular trafficking disruption, endolysosomal dysfunction, mitochondrial issues, and oxidative stress. Current PD models often lack complexity and focus on single phenotypes. We used patient-derived SNCA triplication (SNCA-4x) and isogenic control (SNCA-corr) mDA neurons, applying high-content imaging-based morphological profiling to identify and rescue multiple phenotypes. Screening 1,020 compounds, we identified top-scoring compounds that restored healthy profiles in SNCA-4x neurons, increasing Tyrosine hydroxylase (TH) and decreasing -synuclein (Syn) levels. Several hits were linked to mitochondrial biology. Tyrphostin A9, a mitochondrial uncoupler, and several of its structural analogues decreased ROS levels, normalized mitochondrial membrane potential, and increased respiration. Western blotting confirmed that Tyrphostin A9 reduces Syn levels. Our study highlights the neuroprotective potential of mild mitochondrial uncoupling in mDA neurons.

neuroscience↗

bioRxiv2024

Deep learning-driven neuromorphogenesis screenings identify repurposable drugs for mitochondrial disease

Mitochondrial disease encompasses untreatable conditions affecting tissues with high energy demands. A severe manifestation of mitochondrial disease is Leigh syndrome (Leigh), which causes defects in basal ganglia and midbrain regions, psychomotor regression, lactic acidosis, and early death. We previously generated isogenic pairs of Leigh cerebral organoids and uncovered defects in neuromorphogenesis. Here, we leveraged on this disease feature to devise drug discovery pipelines. We developed a deep learning algorithm tailored for cell type-specific drug repurposing to identify drugs capable of promoting neuronal commitment. In parallel, we performed a survival drug screen in yeast and validated the repurposable hits on branching capacity in Leigh neurons. The two approaches independently highlighted azole compounds, Talarozole and Sertaconazole, both of which lowered lactate release and improved neurogenesis and neurite organization in Leigh midbrain organoids. Hence, targeting neuromorphogenesis has led to identify potential new drugs for mitochondrial disease and could prove an effective strategy for further drug discovery.

neuroscience↗

bioRxiv2020

Enhancing mitochondrial activity in neurons protects against neurodegeneration in CNS inflammation

Central nervous system (CNS) inflammation in multiple sclerosis (MS) drives neuro-axonal loss resulting in irreversible disability. While transcripts of mitochondrial genes are strongly suppressed in neurons during CNS inflammation, it is unknown whether this results in mitochondrial dysfunction and whether interventions that increase mitochondrial function can rescue neurodegeneration. Here we show that suppression of mitochondrial gene transcripts in inflamed neurons was predominantly affecting genes of the electron transport chain resulting in impaired mitochondrial complex IV activity. This was associated with posttranslational inactivation of the transcriptional co-regulator peroxisome proliferator-activated receptor gamma co-activator 1- (PGC-1). Neuronal overexpression of Pgc-1 led to increased numbers of mitochondria, complex IV activity and elevated maximum respiratory capacity. Moreover, Pgc-1- overexpressing neurons showed a higher mitochondrial membrane potential that related to an improved calcium buffering capacity. Accordingly, neuronal deletion of Pgc-1 aggravated neurodegeneration during experimental autoimmune encephalomyelitis (EAE), while neuronal overexpression of Pgc-1 ameliorated EAE disease course and preserved neurons. Our study provides systemic insights into mitochondrial dysfunction in neurons during inflammation and commends elevation of mitochondrial activity as a promising neuroprotective strategy.

neuroscience↗