Biology subjects

Ponomarenko, A.

Publications and source records attributed to Ponomarenko, A..

5 recordsLinked to original sources

bioRxiv2026

Herpes simplex virus infection promotes ALS pathology through ICP0-mediated PML body disruption

Transactive response DNA binding protein 43 kDa (TDP-43) pathology, is a central molecular hallmark of amyotrophic lateral sclerosis (ALS). However, the underlying triggers are incompletely understood. Here, we show that infection with herpes simplex virus (HSV) induces molecular hallmarks of ALS in various in vitro and in vivo models and is associated with an increased risk of ALS in human population data. German healthcare provider data (n = 238,440) and herpesvirus serology of an ALS patient and control cohort (n = 1,100) showed that HSV infection elevated the ALS risk by 210% and odds by [~]65%, respectively. On a molecular level, HSV infection promoted TDP-43 pathology in neuronal cell models, human iPSC-derived motoneurons and cerebral organoids, mice, and human tissue sections. This effect was triggered by HSV-1 or 2, but not by several other related herpesviruses. Mechanistically, the infected cell protein 0 (ICP0) of HSV-1/2 drives TDP-43 pathology by disturbance of promyelocytic leukemia nuclear bodies (PML-NBs), thereby abrogating TDP-43 SUMO2/3ylation. Taken together, we reveal a previously unrecognized association between HSV infection and ALS and clarify the underlying molecular mechanism that drives TDP-43 pathology. Our data may guide future studies into therapeutic and prophylactic interventions against ALS.

neuroscience↗

bioRxiv2025

The NaaS Methodology applied to modeling chemotherapy-induced peripheral neuropathy with human hiPSC neurons

The Neuron-as-a-Sensor (NaaS) methodology is a human-relevant platform designed to detect compound-induced effects by capturing functional changes in neuronal activity. This is achieved by integrating hiPSC-derived neuronal cultures, compartmentalized MEA microfluidic devices, a detailed electrophysiology paradigm and a standardized analysis pipeline. Applied to chemotherapy-induced peripheral neuropathy (CIPN), NaaS leverages electrophysiological profiling to capture alterations in neuronal excitability beyond cytotoxicity. Using paclitaxel and oxaliplatin as reference compounds, we demonstrated drug-specific, time-dependent changes in spontaneous and thermally evoked activity that align with their distinct clinical neuropathic phenotypes. Dimensionality reduction of electrophysiological metrics enabled construction of a functional discrimination map, allowing robust separation of compound signatures from vehicle controls. These findings highlight the ability of NaaS to model clinically relevant neurotoxic effects in a scalable manner, supporting its application in both adverse effect prediction and therapeutic screening.

bioengineering↗

bioRxiv2025

BACE1 regulates sleep-wake cycle through both enzymatic and non-enzymatic actions.

The {beta}-secretase BACE1 has become a prime target in Alzheimers disease (AD) therapy, because it drives the production of pathogenic amyloid {beta} peptides. However, clinical trials with BACE1-targeting drugs were halted due to adverse effects on cognitive performance. We propose here that cognitive impairment by BACE1 inhibitors may be a corollary of a higher function of BACE1 related to proper sleep regulation. To address non-enzymatic effects of BACE1 on ion channels likely involved in the sleep-wake cycle, we analyzed sleep patterns in both BACE1-KO mice and a newly generated transgenic line expressing a proteolysis-deficient BACE1 variant (BACE1-KI). We found that BACE1-KI and BACE1-KO mice displayed common and distinct sleep-wake disturbances. Compared to their respective wild-type littermates, both mutant lines slept less during the light phase (when they preferentially rest). Furthermore, transition rates between wake and sleep states were altered, as were sleep spindles and EEG power spectra mainly in the gamma range. Thus, a better understanding of how BACE1 interferes with sleep-modulated behaviors is needed if clinical trials with BACE1-targeted inhibitors are to resume.

animal behavior and cognition↗

bioRxiv2024

Neurons as biosensors for discriminating neurological disorders in a brain-on-chip platform: Application to Alzheimer s Disease using patient CSF

Alzheimers disease (AD) is characterized by the accumulation of aggregated amyloid beta peptide (A{beta}) leading to progressive neuronal loss and dysfunction. Current ADs diagnosis involves biomarkers assays in cerebrospinal fluid (CSF) as A{beta} to validate the diagnosis. However, these methods are time-consuming, expensive, and can result in inaccurate diagnoses by not accounting for differential diagnose. To overcome these challenges, researchers are exploring new technologies for detecting AD biomarkers in biological fluids, though progress is hindered by an incomplete understanding of AD mechanisms and CSF composition. In this study, we used a standardized microfluidic platform to investigate the effects of synthetic A{beta} peptides and cerebrospinal fluid (CSF) from AD and healthy patients on neuronal functional activity. First, human neurons derived from induced pluripotent stem cells (iPSCs) were characterized. Then, to modulate the functional activity of neurons, tetrodotoxin (TTX), a specific sodium channel blocker, was used as a control for inhibiting neuronal activity. Subsequently, glutamatergic neurons were chronically exposed to A{beta}O and patients CSF. MEA recordings were performed before and after the treatments to assess changes in network activity. Our results demonstrated that extracting key electrophysiological metrics allows for discrimination between healthy and AD CSF samples. This system could offer the potential for differential diagnosis and development of personalized therapeutic strategies.

neuroscience↗

bioRxiv2018

Mutant Plasticity Related Gene 1 (PRG1) acts as a potential modifier in SCN1A related epilepsy

Plasticity related gene 1 encodes a cerebral neuron-specific synaptic transmembrane protein that modulates hippocampal excitatory transmission on glutamatergic neurons. In mice, homozygous Prg1-deficiency results in juvenile epilepsy. Screening a cohort of 18 patients with infantile spasms (West syndrome), we identified one patient with a heterozygous mutation in the highly conserved third extracellular phosphatase domain (p.T299S). The functional relevance of this mutation was verified by in-utero electroporation of a mutant Prg1 construct into neurons of Prg1-knockout embryos, and the subsequent inability of hippocampal neurons to rescue the knockout phenotype on the single cell level. Whole exome sequencing revealed the index patient to additionally harbor a novel heterozygous SCN1A variant (p.N541S) that was inherited from her healthy mother. Only the affected child carried both heterozygous PRG1 and SCN1A mutations. The aggravating effect of Prg1-haploinsufficiency on the epileptic phenotype was verified using the kainate-model of epilepsy. Double heterozygous Prg1-/+|Scn1awt/p.R1648Hmice exhibited higher seizure susceptibility than either wildtype, Prg1-/+, or Scn1awt/p.R1648H littermates. Our study provides evidence that PRG1-mutations have a potential modifying influence on SCN1A-related epilepsy in humans.

neuroscience↗