Biology subjects

Nasrallah, A.

Publications and source records attributed to Nasrallah, A..

6 recordsLinked to original sources

bioRxiv2025

The lipidomic architecture of the mouse brain

Lipids are fundamental components of the brain, crucial for synaptic transmission and signal propagation. Altered brain lipid composition is associated with common and rare neuropathologies, yet, the spatial organization of the mammalian brain lipidome remains insufficiently characterized compared to other modalities1-8. Here, we mapped the membrane lipid architecture of the adult mouse brain at micrometric scale, across sexes, and during pregnancy. This Lipid Brain Atlas reveals that lipids define a fine-grained biochemical structure that aligns with functional anatomy. Membrane lipid spatial heterogeneity clusters into territories, which we termed lipizones. Lipizones partially mirror cell type territories, but also capture distal axon terminals. Through lipizones, (i) we reveal the organizing principles of the gray matter lipidome, related to connectivity and cytoarchitecture; (ii) we discover a new axis of oligodendrocyte heterogeneity in the white matter; (iii) and we find biochemical zonation in the choroid plexus and in the ventricular walls. We show that this lipidomic architecture can adapt to changing physiological needs. In the brain of pregnant females, the white matter is metabolically activated and the outer cortex is reorganized. These results are a foundational resource (https://lbae-v2.epfl.ch/), poised to reshape our understanding of lipids in brain development, physiology, and pathology.

systems biology↗

bioRxiv2025

Type I Interferon Signaling Defines a Novel Disease Signature in Xeroderma Pigmentosum C Human Keratinocytes

Xeroderma Pigmentosum C (XPC) is a DNA damage recognition protein central to the global genome nucleotide excision repair (GG-NER) pathway, where it acts as a primary sensor of UV-induced DNA lesions. Loss-of-function mutations in the XPC gene lead to a photosensitive phenotype, with marked accumulation of unrepaired DNA damage and a dramatically elevated risk (10,000-fold) of skin cancer. However, understanding the molecular signaling mechanisms associated with XP-C has been hindered by the lack of reproducible disease models. Here, we overcome this challenge using our genetically engineered human XPC knockout (KO) keratinocytes, the predominant cell type affected by UV radiation. To uncover upstream signaling changes associated with the absence of XPC expression, we quantified protein tyrosine kinase (PTK) activity one-hour post-UVB exposure. XPC KO keratinocytes showed significant dysregulation of PTK activity on [~]100 phosphosites compared to controls. Complementary mass spectrometry (MS)-based quantitative proteomic analysis performed 24 hours post-UVB exposure identified a downstream signature comprising 791 differentially expressed proteins in XPC KO cells irradiated compared to non-irradiated counterparts. An integrative bioinformatic assessment of the kinase activity and proteomic data revealed a significant perturbation in type I interferon signaling via the JAK/STAT pathway in XPC-deficient keratinocytes, which is further exacerbated by UVB exposure. These findings were validated by western blot analysis, establishing a novel disease-associated molecular signature. Given the central role played by JAK/STAT signaling in inflammatory processes, our results implicate this pathway as a key mediator of XP-Cs hypersensitivity, thereby highlighting its potential as a therapeutic target to alleviate the disease pathology.

molecular biology↗

bioRxiv2025

Molecular Regulation and Physiological Role of 1 GOLPH3-mediated Golgi retention

The Golgi complex serves as the central hub of the biosynthetic pathway, where anterograde and retrograde trafficking converge. How cargo and Golgi-resident proteins traverse this organelle has long been debated. Recent studies have identified a molecular machinery that sorts resident proteins into retrograde-directed COPI vesicles during cisternal maturation. Golgi phosphoprotein 3 (GOLPH3) is a key component of this system; however, its physiological relevance and regulatory mechanisms remain poorly defined. Here, we show that GOLPH3 depletion in mice disrupts both protein and lipid glycosylation, causes partially penetrant embryonic lethality, and severely impairs growth and bone mineralization. At the molecular level, we find that GOLPH3 is regulated by functionally antagonistic S-acylation events that control the topology of its membrane association. To mediate retrograde trafficking of Golgi-resident glycosyltransferases, GOLPH3 must bind their cytosolic tails. This occurs via a negatively charged surface region, which is correctly oriented only in one of the S-acylated GOLPH3 conformations. Together, these findings reveal a lipid-mediated regulatory mechanism for intra-Golgi trafficking and establish the critical role of GOLPH3 in vertebrate development.

cell biology↗

bioRxiv2024

Generation and characterization of CRISPR-Cas9-Mediated XPC Gene Knockout in Human Skin Cells

Xeroderma pigmentosum group C (XPC) is a versatile protein, crucial for sensing DNA damage in the global genome nucleotide excision repair (GG-NER) pathway. This pathway is vital for mammalian cells, acting as their essential approach for repairing DNA lesions stemming from interactions with environmental factors, such as exposure to ultraviolet (UV) radiation from the sun. Loss-of-function mutations in the XPC gene confer a photosensitive phenotype in XP-C patients with the accumulation of unrepaired UV induced DNA damage. This remarkable increase in DNA damage tends to elevate by 10,000-fold the risk of developing melanoma and non-melanoma skin cancers. To date, creating accurate and reproducible models to study human XP-C disease has been an important challenge. To tackle this, we used CRISPR-Cas9 technology in order to knockout XPC gene in various human skin cells (keratinocytes, fibroblasts, and melanocytes). After validation of the XPC knockout in these edited skin cells, we showed that they recapitulate the major phenotypes of XPC mutations: photosensitivity and the impairment of UV induced DNA damage repair. Moreover, these mutated cells demonstrated a reduced proliferative capacity compared to their respective wild-type controls. Finally, to better mimic the disease environment, we built a 3D reconstructed skin using these XPC knockout skin cells. This model exhibited an abnormal behavior, showing an extensive remodeling of its extracellular matrix compared to normal skin. Analyzing the composition of the fibroblasts secretome revealed a significant augmented shift in the inflammatory response following XPC knockout. Our innovative "disease on a dish" approach can provide valuable insights into the molecular mechanisms underlying XP-C disease, paving the way to design novel preventive and therapeutic strategies to alleviate the disease phenotype. Also, given the high risk of skin cancer onset in XP-C disease, our new approach can also serve as a link to draw novel insights towards this elusive field.

genetics↗

bioRxiv2022

Neuromorphic Model of Hippocampus Place cells using an Oscillatory Interference Technique for Hardware Implementation

In this paper, we propose a simplified and robust model for Place cell generation based on the Oscillatory Interference (OI) model concept. Aiming toward hardware implementation in bio-inspired Simultaneous Localization and Mapping (SLAM) systems for mobile robotics, we base our model on logic operations that reduce its computational complexity. The model compensates for parameter variations in the behaviors of the population of constituent Theta cells, and allows the Theta cells to have square-wave oscillation profiles. The robustness of the model, with respect to mismatch in the Theta cells base oscillation frequency and gain--as a function of modulatory inputs--is demonstrated. Place cell composed of 48 Theta cells with base frequency variations with a 25% standard deviation from the mean and a gain error with 20% standard deviation from the mean only result in a 20% deformations within the place field and 0.24% outer side lobes, and an overall pattern with 0.0015 mean squared error on average. We also present how the model can be used to achieve the localization and path-tracking functionalities of SLAM.

neuroscience↗

bioRxiv2019

PamgeneAnalyzeR open and reproducible pipeline for kinase profiling

Protein phosphorylation - catalyzed by protein kinases - is the most common post-translational modification. It increases the functional diversity of the proteome and influences various aspects of normal physiology and can be altered in disease states. High throughput profiling of kinases is becoming an essential experimental approach to investigate their activity and this can be achieved using technologies such as PamChip(R) arrays provided by PamGene for kinase activity measurement. Here we present \"pamgeneAnalyzeR\", an R package developed as an alternative to the manual steps necessary to extract the data from PamChip(R) peptide microarrays images in a reproducible and robust manner. The extracted data can be directly used for downstream analysis.\n\nAvailability and implementationPamgeneAnalyzeR is implemented in R and can be obtained from https://github.com/amelbek/pamgeneAnalyzeR.

bioinformatics↗