Biology subjects

Younas, N.

Publications and source records attributed to Younas, N..

3 recordsLinked to original sources

bioRxiv2025

Tau oligomer heterogeneity and associated protein profile in slowly versus rapidly progressive Alzheimer's disease

Rapidly progressive Alzheimers disease (rpAD) is a rare but devastating clinical variant characterized by abrupt cognitive decline, yet the molecular features underlying this phenotype remain unknown. Tau oligomers (TauO) are key mediators of tau toxicity, but whether their biochemical properties differ across AD subtypes has not been examined in human brain. We isolated endogenous TauO from frontal cortex of well-characterized control, slowly progressive AD (spAD), and rpAD cases using T22 immunoprecipitation and performed ultrastructural, biochemical, and proteomic characterization. rpAD TauO displayed compact, densely aggregated morphology and exhibited the highest levels of disease-associated phosphorylation (pS396, pS422). Label-free proteomics revealed that control and spAD shared a robust TauO interactome enriched for translation, proteostasis, mitochondrial metabolism, and vesicle trafficking. Strikingly, these modules were absent in rpAD, which instead showed selective enrichment for aldehyde detoxification, amino-acid and carbon metabolism, and actin-regulatory pathways. rpAD TauO demonstrated increased association with SERPINA1, ALDH9A1, MAPRE3, DPYSL2/3, and NFASC, and reduced association with MRPL17 and C9. Functionally, rpAD TauO induced the strongest toxicity in SH-SY5Y cells. Together, these findings indicate that rpAD likely harbors a biochemically distinct TauO species, defining a molecular signature that may underpin its fulminant clinical progression and support the development of subtype-specific therapeutic strategies.

neuroscience↗

bioRxiv2025

Proteomic and Kinetic Characterization of Prion Seeding in Distinct Human CJD Strains Unveils Early Diagnostic Biomarkers

To enhance understanding of early diagnosis, differential disease progression rates, and the molecular profiles of human prion strains, we analyzed prion seeding activity over time in Creutzfeldt-Jakob disease (CJD)-infected mice using the real-time quaking-induced conversion (RT-QuIC) assay. Our previous work highlighted pre- clinical alterations in endocytic machinery and cytoskeleton-associated responses in CJD-affected brain regions. In this study, infectious prion strains derived from human CJD-MM1 and VV2 brain tissues were inoculated into tg340, tg361 (expressing approximately four times the human PrP-M129 and PrP-V129, respectively), and tg650 (expressing approximately six times the human PrP-M129) mice. A total of 188 brain samples (cortex) were analyzed from confirmed CJD-infected mice and control mice at both pre-clinical and clinical stages of the disease. Notably, we observed region- specific and PrP strain-specific differences in seeding activity at the pre-clinical stage of disease in CJD-MM1 and VV2 infected mice. The lag phase between the positive response ranged from 7.5 to 24.5 hours across all regions and disease stages. In the cortex, CJD-MM1-infected tg340 mice exhibited a prolonged lag phase ([~]24.5 hours), while CJD-VV2-infected tg341 mice showed minimal seeding response and relative fluorescence unit (RFU) signal rates. In contrast, the cerebellum of VV2 clinical stage mice exhibited a shorter lag phase, and VV2 preclinical stage mice showed significantly lower RFU signal rates. Proteomic profiling via SWATH-MS identified 500 and 682 differentially expressed proteins in the MM1 and VV2 models, respectively. Key proteins such as Gnl1, Stxbp1, Pllp, Gps1, Nefh, Ahsa1, Rala, Cacybp, Pdk1, Unc13a, Rab21, Rraga, Ppp1r9a, Eif4b, Atp2b2, Vps51, H2afx in CJD-MM1 and Gm10358, Tnc, Calb2, Ppm1h, Dnaja1, Gm45808, Hpcal1, Prkca, Dock3, Syn2, Agap2, Tmem126a, Fdps, Ndufa4 in CJD- VV2 showed significant alterations at the early pre-clinical stages, correlating with detectable prion replication. These molecular shifts highlight potential early-stage diagnostic biomarkers. Functional analyses revealed that both MM1 and VV2 subtypes engage early compensatory responses; however, MM1 primarily involves metabolic reprogramming and enhanced vesicle clearance, while VV2 is characterized by pronounced disturbances in calcium signaling and structural integrity at early stage of the disease. These findings emphasize the utility of RT-QuIC and proteomics in characterizing prion seeding and progression, providing valuable insights into the molecular mechanisms underlying prion diseases and potential early diagnostic markers.

neuroscience↗

bioRxiv2025

Molecular and structural remodeling of stress granules in slowly and rapidly progressive Alzheimer's disease

Stress granules (SGs) are dynamic ribonucleoprotein condensates that modulate RNA metabolism during cellular stress. Although SG dysfunction has been increasingly linked to neurodegenerative diseases, their structural and molecular remodeling in Alzheimers disease (AD), particularly rapidly progressive AD (rpAD), remains poorly understood. Here, we present a comprehensive multi-omics characterization of SGs from postmortem frontal cortex tissues of control, slowly progressive AD (spAD), and rpAD subjects. SGs were immunoprecipitated using Anti-TIAR antibodies and analyzed via transmission electron microscopy (TEM), LCMS/MS-based proteomics, and RNA sequencing. Key protein findings were validated in human cortical brain homogenates and a 3xTg mouse model of A{beta} and tau pathology. TEM revealed disease-specific SG morphologies: small spherical granules in controls; moderate clustering in spAD; and large, amorphous aggregates in rpAD. Proteomic profiling identified 1,667 high-confidence SG-associated proteins, including RNA-binding proteins and disease-linked proteins such as MAPT, APP, and SNCA. SGs in rpAD were significantly enriched for pathways involved in MAPK signaling, proteostasis, and neuroinflammation, while showing reduced abundance of key cytoskeletal and translational regulators, such as TUBA1B and EEF1A2. Transcriptome analysis revealed widespread depletion of long, GC-rich, protein coding RNAs in rpAD SGs. Notably dynamic dysregulation of TUBA1B was also observed in the 3xTg mouse model and human cortical tissues, highlighting cytoskeletal vulnerability during disease progression. Together, these findings uncover profound structural and molecular remodeling of SGs in AD, with rpAD exhibiting a distinctive shift towards pathological SG composition and function. Our results highlight a link between SG alterations and aggressive AD subtypes, providing new mechanistic insights and suggesting new potential targets for therapeutic intervention.

neuroscience↗