Biology subjects

Fabrik, I.

Publications and source records attributed to Fabrik, I..

5 recordsLinked to original sources

bioRxiv2026

Aging-associated endo-lysosomal dysfunction drives inflammaging and neurodegeneration through the STING-IFN-I axis

All animals age. However, aging is a heterogeneous process and individual organisms age differently. Moreover, within the same organism, cells or organs do not age at the same time or speed. For instance, although neurodegeneration is a key trait of aging, neurological symptoms normally manifest long after multiple indicators of aging in peripheral tissues. The genetic determinants of aging remain poorly understood. Mutations in leucine-rich repeat kinase 2 (LRRK2) are major genetic risk factors for Parkinsons disease (PD). By analyzing PD patients and mice with LRRK2 gain of function mutation (LRRK2GoF), we demonstrate that PD is an accelerated aging disease characterized by systemic low-grade STING-dependent inflammation (inflammaging) that first manifests in the periphery then disrupts the blood brain barrier and progresses to the brain resulting in neurodegeneration. Mechanistically, we demonstrate that a primary consequence of aging or Lrrk2GoF is endolysosomal decline. This results in the cytosolic build-up of extraneous self-DNA and subsequent shedding of DNA-containing extracellular vesicles thereby triggering the cGAS- STING pathway cell-intrinsically and intercellularly in distant host cells. This study unveils the cGAS-STING pathway and LRRK2GoF as key determinants and potential targets for preventive or therapeutic strategies against accelerated aging, inflammaging and neurodegeneration.

immunology↗

bioRxiv2025

Viral Infection Induces Alzheimer's Disease-Related Pathways and Senescence in iPSC-Derived Neuronal Models

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSThe Pathogen Infection Hypothesis proposes that {beta}-Amyloid (A{beta}) functions as an antimicrobial peptide, with pathogen-induced aggregation potentially contributing to Alzheimers disease (AD) pathology. METHODSWe used human iPSC-derived 2D neurons and 3D cerebral organoids from wild-type and familial AD (PSEN1/2 mutant) lines to model acute infections with HSV-1 and TBEV and A{beta} aggregation. Transcriptomic and proteomic analyses were conducted to assess molecular responses. RESULTSHSV-1, but not TBEV, induced robust A{beta} clustering, which was, however, dependent on extracellular amyloid peptides. Transcriptomic profiling revealed widespread HSV-1-induced changes, including activation of neurodegeneration-related pathways. Proteomic profiling confirmed enrichment of neurodegeneration- and senescence-associated secretome signatures. PSEN1/2 mutations did not alter the acute infection response. Reanalysis of independent datasets confirmed our findings and revealed a limited protective effect of acyclovir. DISCUSSIONResults directly support the Pathogen Infection Hypothesis and suggest that preventing viral infections via vaccinations may represent a feasible approach to reducing AD risk.

neuroscience↗

bioRxiv2025

New insights into the 17β-hydroxysteroid dehydrogenase type 10 and amyloid-β 42 derived cytotoxicity relevant to Alzheimer's disease

The multifunctional mitochondrial enzyme 17{beta}-hydroxysteroid dehydrogenase type 10 (HSD10) plays an important role in the pathology of several diseases, of which Alzheimers disease (AD) is the most debated. HSD10 overexpression and its interplay with amyloid-{beta} peptide (A{beta}) are considered a factor contributing to mitochondrial damage and neuronal stress observed in AD patients. This study confirms that individual overexpression of HSD10 or APP (amyloid precursor protein that gives rise to A{beta}) leads to cytotoxicity, and both pathological conditions are linked to mitochondrial damage. However, the metabolic changes caused by these two overexpressions significantly differ, particularly in their effect on the tricarboxylic acid cycle and {beta}-oxidation. Furthermore, the enzymatic activity of HSD10 is identified as the primary factor of HSD10 cytotoxicity, which is significantly exacerbated in an A{beta}-rich environment and can be partially reversed by HSD10 inhibitors. Notably, a previously published and competitive benzothiazole inhibitor was effective in restoring the viability of HSD10 overexpressing cells alone and in an A{beta}-rich environment, implying the potential benefit of HSD10 inhibitors in mitochondrial diseases and/or AD treatment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/639531v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@319d63org.highwire.dtl.DTLVardef@153e439org.highwire.dtl.DTLVardef@ac6a40org.highwire.dtl.DTLVardef@173aede_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Loss of Lamin A leads to the nuclear translocation of AGO2 and compromised RNA interference

In mammals, RNA interference (RNAi) was historically studied as a cytoplasmic event; however, in the last decade, a growing number of reports convincingly show the nuclear localization of the Argonaute (AGO) proteins. Nevertheless, the extent of nuclear RNAi and its implication in biological mechanisms remain to be elucidated. We found that reduced Lamin A levels significantly induce nuclear influx of AGO2 in SHSY5Y neuroblastoma and A375 melanoma cancer cell lines, which normally have no nuclear AGO2. Lamin A KO manifested a more pronounced effect in SHSY5Y cells compared to A375 cells, evident by changes in cell morphology, increased cell proliferation, and oncogenic miRNA expression. Furthermore, in SHSY5Y cells, AGO fPAR-CLIP in Lamin A KO cells revealed significantly reduced activity of RNAi. Further exploration of the nuclear AGO interactome by mass spectrometry indicated that AGO2 is in complex with FAM120A, an RNA-binding protein and known interactor of AGO2. By performing FAM120A fPAR-CLIP, we discovered that FAM120A co-binds AGO targets and that this competition reduces the activity of RNAi. Therefore, loss of Lamin A triggers nuclear AGO2 translocation, RNAi impairment, and selective upregulation of oncogenic miRNAs, facilitating cancer cell proliferation.

biochemistry↗

bioRxiv2022

Lung macrophages utilize cathepsin K-dependent phagosomal machinery to degrade intracellular collagen

Resident tissue macrophages (RTMs) are organ-specialized phagocytes responsible for the maintenance and protection of tissue homeostasis. It is well established that tissue diversity is reflected by the heterogeneity of RTMs origin and phenotype. However, much less is known about tissue-specific phagocytic and proteolytic macrophage functions. Here, using quantitative proteomics approach, we identify cathepsins as key determinants of phagosome maturation in primary peritoneal, lung and brain resident macrophages. The data further uncover cathepsin K (CtsK) as a molecular marker for lung phagosomes required for intracellular protein and collagen degradation. Pharmacological blockade of CtsK activity diminished phagosomal proteolysis and collagenolysis in lung resident macrophages. Furthermore, pro-fibrotic TGF-{beta} negatively regulated CtsK-mediated phagosomal collagen degradation independently from classical endocytic proteolytic pathways. In humans, phagosomal CtsK activity was reduced in COPD lung macrophages and non-COPD lung macrophages exposed to cigarette smoke extract. Taken together, this study provides a comprehensive map of how peritoneal, lung and brain tissue environment shapes phagosomal composition, revealing CtsK as a key molecular determinant of lung phagosomes contributing to phagocytic collagen clearance in lungs.

cell biology↗