Biology subjects

Abdelhak, A.

Publications and source records attributed to Abdelhak, A..

6 recordsLinked to original sources

bioRxiv2026

Innate Immune Dysregulation Precedes Clinical Onset in Neuromyelitis Optica

Neuromyelitis optica spectrum disorder (NMOSD) is a disabling inflammatory central nervous system (CNS) disease characterized by pathogenic aquaporin 4 (AQP4) autoantibodies. The biological events that precede clinical onset remain unknown. In a unique longitudinal NMOSD cohort from the U.S. Department of Defense Serum Repository, with samples collected up to 24 years before onset, we applied discovery proteomics (~5,400 proteins), pan-viral antibody profiling (VirScan), and in silico analyses to characterize preclinical NMOSD versus matched healthy controls. Innate immune activation, particularly CXCL1 elevation, was the dominant immunological feature of preclinical NMOSD, preceding onset by ~12.7 years. AQP4-IgG was detectable more than 3 years before onset, while CNS injury markers increased only after disease manifestation. VirScan identified enhanced CMV-specific antibody reactivity following AQP4- IgG seroconversion, and network analyses revealed interactions between NMOSD-associated and CMV-derived proteins. Together, these findings establish a novel multi-hit model of NMOSD, with implications for understanding antibody-mediated autoimmunity more broadly.

immunology↗

bioRxiv2026

Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD), predominantly comprised of tau and TDP-43 proteinopathies, is a common cause of early-onset dementia. Biomarkers that reliably classify FTLD subtypes are limited, thereby hindering in-vivo diagnosis and clinical trial stratification. We conducted large-scale, multi-platform cerebrospinal fluid proteomics in 566 individuals, including 274 FTLD-spectrum (48 autopsy-confirmed FTLD-TDP, 90 autopsy-confirmed FTLD-tau), 171 Alzheimers disease, and 95 controls. In neuropathological subtype contrasts, elevated matrix metalloproteinase MMP10 classified Picks disease (PiD) versus other subtypes with near-perfect accuracy across proteomic platforms. We further validated CSF MMP10 as a potential PiD diagnostic biomarker via a targeted immunoassay in an independent, autopsy-confirmed FTLD cohort. Post-synaptic proteins HOMER1 and DLG4 exhibited elevations across FTLD-TDP subtypes (A, B, and C) versus FTLD-tau. Network analysis identified RNA metabolism and pro-inflammatory signatures in FTLD-TDP, and cytoskeletal and heat shock signatures in progressive supranuclear palsy. These findings reveal candidate diagnostic biomarkers and proteomic pathways underlying FTLD clinico-pathological heterogeneity.

neuroscience↗

bioRxiv2026

Protein Predictors of Worsening Cerebral Edema in Traumatic Brain Injury in Critically Ill Patients

Cerebral edema (CE) is a major determinant of poor outcomes after traumatic brain injury (TBI). CE affects approximately 60% of patients with mass lesions on head computed tomography (hCT) and confers a tenfold increase in mortality. Despite this burden, no validated biomarkers exist to identify patients at risk for early CE worsening or to elucidate the biological processes underlying divergent edema trajectories. We conducted high-throughput plasma proteomic profiling in a prospective moderate-severe TBI cohort with evidence of intracranial blood on the initial post-injury hCT scan (n=123 patients) to (1) identify a clinically feasible set of biomarkers plus a predictive model that could be used to assess CE risk at admission, and (2) conduct a mechanistic, hypothesis-generating analysis to identify the molecular networks involved in CE progression in the first hours post-injury. Plasma collected within 3 hours of injury was analyzed using the Olink Explore platform (5394 proteins), and patients underwent head CT imaging upon presentation and at 6 hours. Two complementary analytic pathways, reflecting the studys two goals, were pursued in parallel. First, logistic regression with false discovery rate (FDR) correction identified a conservative 12-protein set associated with baseline CE. When combined with targeted clinical variables (i.e., age, sex, admission GCS, pupil reactivity, admission glucose, admission alcohol), this panel supported high-performing supervised classifiers for predicting CE worsening by 6 hours post-baseline scan (best model: XGBoost, AUC = 0.78; recall = 0.83). Second, a broader 60-protein panel, selected via bootstrapped elastic-net regression, was used to interrogate the mechanistic architecture of CE worsening using random forest SHAP attribution and protein-protein interaction modeling. Proteomic signatures diverged sharply between patients whose CE did and did not worsen. The CE worsening group was characterized by a coherent neuronal-synaptic injury axis dominated by ELAVL4, CEND1, NEFL, NECAB2, GFAP, CHGB, RPH3A, HPCAL4, and HOMER1, proteins involved in neuronal structural integrity, vesicular trafficking, synaptic vesicle cycling, calcium signaling, and axonal degeneration. These reciprocal proteomic states suggest that early edema progression may be driven by coordinated disruption of neuronal and synaptic resilience programs. Together, these findings suggest (1) a hyperacute biomarker panel plus predictive model with potential for prospective validation and (2) mechanistic evidence for a distinct neuronal-synaptic injury network that associates with early edema worsening after TBI.

neuroscience↗

bioRxiv2024

Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia

Mutations in progranulin (GRN) cause frontotemporal dementia (GRN-FTD) due to deficiency of the pleiotropic protein progranulin. GRN-FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN-FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn-/- mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn-/- RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

neuroscience↗

bioRxiv2023

Remyelination protects neurons from DLK-mediated neurodegeneration

Chronic demyelination and oligodendrocyte loss deprive neurons of crucial support. It is the degeneration of neurons and their connections that drives progressive disability in demyelinating disease. However, whether chronic demyelination triggers neurodegeneration and how it may do so remain unclear. We characterize two genetic mouse models of inducible demyelination, one distinguished by effective remyelination and the other by remyelination failure and chronic demyelination. While both demyelinating lines feature axonal damage, mice with blocked remyelination have elevated neuronal apoptosis and altered microglial inflammation, whereas mice with efficient remyelination do not feature neuronal apoptosis and have improved functional recovery. Remyelination incapable mice show increased activation of kinases downstream of dual leucine zipper kinase (DLK) and phosphorylation of c-Jun in neuronal nuclei. Pharmacological inhibition or genetic disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. Together, we demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as protective strategy for chronically demyelinated neurons. HighlightsO_LICharacterization of a transgenic mouse model of demyelination without subsequent remyelination C_LIO_LIRemyelination protects neurons from axon loss and neuronal apoptosis C_LIO_LIMAPK and c-Jun phosphorylation are increased in mice featuring remyelination failure C_LIO_LIDLK is necessary for the apoptosis of chronically demyelinated neurons C_LI

neuroscience↗

bioRxiv2023

A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain

The mammalian brain is composed of millions to billions of cells that are organized into numerous cell types with specific spatial distribution patterns and structural and functional properties. An essential step towards understanding brain function is to obtain a parts list, i.e., a catalog of cell types, of the brain. Here, we report a comprehensive and high-resolution transcriptomic and spatial cell type atlas for the whole adult mouse brain. The cell type atlas was created based on the combination of two single-cell-level, whole-brain-scale datasets: a single- cell RNA-sequencing (scRNA-seq) dataset of [~]7 million cells profiled, and a spatially resolved transcriptomic dataset of [~]4.3 million cells using MERFISH. The atlas is hierarchically organized into five nested levels of classification: 7 divisions, 32 classes, 306 subclasses, 1,045 supertypes and 5,200 clusters. We systematically analyzed the neuronal, non-neuronal, and immature neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell type organization in different brain regions, in particular, a dichotomy between the dorsal and ventral parts of the brain: the dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. We also systematically characterized cell-type specific expression of neurotransmitters, neuropeptides, and transcription factors. The study uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types across the brain, suggesting they mediate a myriad of modes of intercellular communications. Finally, we found that transcription factors are major determinants of cell type classification in the adult mouse brain and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole-mouse-brain transcriptomic and spatial cell type atlas establishes a benchmark reference atlas and a foundational resource for deep and integrative investigations of cell type and circuit function, development, and evolution of the mammalian brain.

neuroscience↗