Biology subjects

Jagannath, S.

Publications and source records attributed to Jagannath, S..

6 recordsLinked to original sources

bioRxiv2026

SIRT6 Activation Improves Intervertebral Disc Health in the Aging Spine

Aging is one of the most important risk factors for Intervertebral disc degeneration, a major contributor to chronic low back and neck pain. Recently, we demonstrated a critical role for SIRT6, a nuclear NAD- dependent deacetylase and defatty acylase, in maintaining intervertebral disc health with aging. We therefore investigated whether pharmacological activation of SIRT6 improves disc health by examining the spinal phenotype of 24-month-old mice treated with the well-studied agonist MDL-800 for 6 months. Histological studies revealed healthy disc tissue morphology, enhanced cell viability, and lower degeneration scores in mice treated with MDL-800. Further mechanistic insights revealed that SIRT6 activation decreased H3K9ac levels, improved cell phenotype and matrix quality, and reduced the SASP burden in the disc, characterized by decreased abundance of p21, IL-6, and TGF-{beta}. Tissue RNA-Seq, in vitro measurements of histone 3 modifications, and multi-omics ATAC-seq/RNA-seq analyses revealed that SIRT6 activation altered the epigenetic status (decreased H3K9ac, H3K36me3, and H3K79me2) and transcriptomic landscape of disc cells. Notably, MDL-800 treatment increased LC3II levels in disc cells, indicating enhanced autophagic flux. Furthermore, plasma LC-MS and nuclear magnetic resonance (NMR) analyses revealed minimal systemic metabolomic changes. ScRNA-sequencing of splenocytes and bone marrow cells and systemic cytokine profiling indicated good tolerance and the absence of systemic inflammation following MDL-800 treatment. Our study demonstrates that SIRT6 activation modulates autophagy, cell senescence, and matrix homeostasis in the disc, underscoring the feasibility of targeting SIRT6 activation as a promising pharmacological strategy to maintain disc health in the aging spine.

biochemistry↗

bioRxiv2025

Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes

Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) shows striking clinical and neuropathological heterogeneity, yet a systematic analysis of subtype-specific features and inter-patient variability was missing. We treated human neurons and neuron-like cells with 30 postmortem brain samples and quantified neoaggregate formation, loss of function and changes in the TDP-43 interactome to define determinants of seeding outcomes. Potent FTLD-TDP-A seeds drove a progressive collapse of physiological TDP-43 interactions accompanied by functional loss. Beyond the burden of pathological TDP-43, we identified the fibrillar core of the lysosomal protein TMEM106B as a critical pro-seeding factor. Transient lysosomal injury markedly enhanced neoaggregation and loss of function, likely by promoting fibril interactions with native TDP-43. Our work establishes a mechanistic link between TMEM106B and TDP-43 aggregation, identifies lysosomal escape as a key driver of pathology and introduces the strongest model yet for seeded TDP-43 aggregation and loss of function, to enable discovery of disease modifiers.

neuroscience↗

bioRxiv2024

Dissecting the differential role of C-terminal truncations in the regulation of aSyn pathology formation and the biogenesis of Lewy bodies

Alpha-synuclein (aSyn) post-translational modifications (PTMs), particularly phosphorylation at serine 129 and C-terminal truncations, are highly enriched in Lewy bodies (LBs), Lewy neurites, and other types of aSyn pathological aggregates in the brain of patients with Parkinsons disease (PD) and other synucleinopathies. However, our knowledge about the precise role of PTMs in regulating the different stages of pathology formation, neurodegeneration, and aSyn pathology spreading remains incomplete. In this work, we applied a systematic approach to address this knowledge gap with an emphasis on mapping and elucidating the role of post-fibrillization C-terminal aSyn truncations in regulating the uptake, processing, seeding activity, and formation of LB-like inclusions and maturations in a well-established neuronal seeding model that recapitulates all the stages leading to LB formation and neurodegeneration. Our work shows that C-terminal cleavage of aSyn fibrils at multiple sites is a conserved process that occurs rapidly after and during the formation of intracellular LB-like aSyn inclusions in all neuronal seeding models. Interestingly, blocking the cleavage of internalized fibrils does not influence their seeding activity, whereas inhibiting the enzymes that regulate the cleavage of newly formed fibrils (e.g., calpains 1 and 2) significantly alters the formation of LB-like inclusions. We also show that C-terminal truncations, in combination with other PTMs, play a crucial role in regulating the interactome and remodeling of newly formed aSyn fibrils, including their shortening, lateral association, and packing during LB formation and maturation. Altogether, our results demonstrate that post-fibrillization C-terminal truncations have a differential role at different stages of aSyn aggregation and pathology formation. These insights, combined with the abundance of truncated aSyn species in LBs, have significant implications in understanding aSyn pathological diversity and developing therapeutic strategies targeting the C-terminus of aSyn or its proteolytic processing.

neuroscience↗

bioRxiv2022

Development and validation of an expanded antibody toolset that captures alpha-synuclein pathological diversity in Lewy body diseases

The abnormal aggregation and accumulation of alpha-synuclein (aSyn) in the brain is a defining hallmark of synucleinopathies. Different aSyn conformations and post-translationally modified forms accumulate in pathological inclusions and vary in abundance across synucleinopathies. Relying on antibodies that have not been assessed for their ability to capture the diversity of aSyn species may not provide an accurate estimation of aSyn pathology in human brains or disease models. To address this challenge, we developed and characterised an expanded antibody panel that targets different sequences and post-translational modifications along the length of aSyn and recognises all three aSyn conformations (monomeric, oligomeric, fibrillar). Next, we profiled aSyn pathology across sporadic and familial Lewy body diseases (LBDs) and reveal heterogeneously modified aSyn pathologies rich in Serine 129 phosphorylation but also in Tyrosine 39 nitration and N- and C-terminal tyrosine phosphorylations, scattered to neurons and glia. We also show that aSyn may become hyperphosphorylated during the aggregation and inclusion maturation processes in neuronal and animal models of aSyn aggregation and spreading. The antibody validation pipeline we describe here paves the way for more systematic investigations of aSyn pathological diversity in the human brain and peripheral tissues, and in cellular and animal models of synucleinopathies.

neuroscience↗

bioRxiv2020

Characterization and validation of 15 α-synuclein conformation-specific antibodies using well-characterized preparations of α-synuclein monomers, fibrils and oligomers with distinct structures and morphology: How specific are the conformation-specific α-synuclein antibodies?

Increasing evidence suggests that alpha-synuclein (-syn) oligomers are obligate intermediates in the pathway involved in -syn fibrillization and Lewy body (LB) formation, and may also accumulate within LBs in Parkinsons disease (PD) and other synucleinopathies. Therefore, the development of tools and methods to detect and quantify -syn oligomers has become increasingly crucial for mechanistic studies to understand the role of these oligomers in PD, and to develop new diagnostic methods and therapies for PD and other synucleinopathies. The majority of these tools and methods rely primarily on the use of aggregation state-specific or conformation-specific antibodies. Given the impact of the data and knowledge generated using these antibodies on shaping the foundation and directions of -syn and PD research, it is crucial that these antibodies are thoroughly characterized, and their specificity or ability to capture diverse -syn species is tested and validated. Herein, we describe an antibody characterization and validation pipeline that allows a systematic investigation of the specificity of -syn antibodies using well-defined and well-characterized preparations of various -syn species, including monomers, fibrils, and different oligomer preparations that are characterized by distinct morphological, chemical and secondary structure properties. This pipeline was used to characterize 18 -syn antibodies, 16 of which have been reported as conformation- or oligomer-specific antibodies, using an array of techniques, including immunoblot analysis (slot blot and Western blot), a digital ELISA assay using single molecule array technology and surface plasmon resonance. Our results show that i) none of the antibodies tested are specific for one particular type of -syn species, including monomers, oligomers or fibrils; ii) all antibodies that were reported to be oligomer-specific also recognized fibrillar -syn; and iii) a few antibodies showed high specificity for oligomers and fibrils but did not bind to monomers. These findings suggest that the great majority of -syn aggregate-specific antibodies do not differentiate between oligomers and fibrils, thus highlighting the importance of exercising caution when interpreting results obtained using these antibodies. Our results also underscore the critical importance of the characterization and validation of antibodies before their use in mechanistic studies and as diagnostic and therapeutic agents. This will not only improve the quality and reproducibility of research and reduce costs but will also reduce the number of therapeutic antibody failures in the clinic.

neuroscience↗

bioRxiv2020

Patient Similarity Network of Newly Diagnosed Multiple Myeloma Identifies Patient Sub-groups with Distinct Genetic Features and Clinical Implications

The remarkable genetic heterogeneity of Multiple Myeloma (MM) poses a significant challenge for proper prognostication and clinical management of patients. Accurate dissection of the genetic and molecular landscape of the disease and the robust identification of homogeneous classes of patients are essential steps to reliable risk stratification and the development of novel precision medicine strategies. Here we introduce MM-PSN, the first multi-omics Patient Similarity Network of newly diagnosed MM. MM-PSN has enabled the identification of three broad patient groups and twelve distinct sub-groups defined by five data types generated from genomic and transcriptomic patient profiling of 655 patients. The MM-PSN classification uncovered novel associations between distinct MM hallmarks with significant prognostic implications and allowed further refinement of risk stratification. Our analysis revealed that gain of 1q is the most important single lesion conferring high risk of relapse, and its association with an MMSET translocation is the most significant determinant of poor outcome. We developed a classifier and validated these results in an independent dataset of 559 pts. Our findings suggest that gain of 1q should be incorporated in routine staging systems and risk assessment tools. The MM-PSN classifier is available as a free resource to allow for an easy implementation in most clinical settings.

cancer biology↗