Biology subjects

Nirujogi, R.

Publications and source records attributed to Nirujogi, R..

3 recordsLinked to original sources

bioRxiv2026

Distinct mechanistic pathways of early tauopathy revealed by MAPT mutations

Tau pathology underlies a broad spectrum of neurodegenerative disorders, collectively termed tauopathies, yet these diseases exhibit striking heterogeneity in their biological mechanisms and clinical outcomes. The basis for this heterogeneity remains poorly understood. Here, we address this question using knock-in mouse models expressing two distinct frontotemporal dementia-associated tau mutations to define how different tau variants drive divergent pathogenic programs in vivo. We find that the two mutations give rise to fundamentally different trajectories of tau pathogenesis. One trajectory is marked by progressive tau hyperphosphorylation and cytoskeletal destabilization occurring in the absence of detectable tau seed formation. In contrast, an alternative trajectory is characterized by tau hypophosphorylation, early seed formation, and alterations in nucleotide metabolism and chromatin organization, without overt cytoskeletal disruption. With aging, tau in this latter pathway transitions to a hyperphosphorylated state and forms mature fibrillar aggregates. Genetic enhancement of {beta}-amyloid selectively accelerates fibril formation, particularly in the model exhibiting early seeding. Together, these findings demonstrate that distinct tau mutations can engage separable pathogenic mechanisms, providing a biological framework for the heterogeneity observed across tauopathies, and highlighting the need for mechanism-informed therapeutic strategies and patient stratification. O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/705716v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@11eb652org.highwire.dtl.DTLVardef@153cc53org.highwire.dtl.DTLVardef@8b670eorg.highwire.dtl.DTLVardef@1afaad_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstractSchematic representation comparing two trajectories of tau pathology. The S305N mutation promotes a 4R isoform shift, cytoskeletal damage and synapse loss, and accumulation of soluble hyperphosphorylated tau. Tau remains soluble even at old ages. In contrast, the P301S mutation generates hypophosphorylated, seed-competent tau that forms fibrils. The effect of amyloid is slow in the S305N, but results in accelerated acceleration of pathology in the P301S. Figure made with Biorender.com.

neuroscience↗

bioRxiv2025

TDP-43 loss of function drives aberrant splicing in Parkinson's disease

Introductory paragraphWhile mRNA splicing dysregulation is a well-established contributor to neurodegeneration in disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), its role in Parkinsons disease (PD) remains underexplored. Here, we analyse transcriptomic data from >500 post-mortem human brain samples from individuals with and without PD to show that splicing alterations are frequently detected. Differentially spliced genes were significantly more enriched for those causally-implicated in both PD and ALS than genes that were differentially expressed. Furthermore, we observed a strong association between these splicing alterations and dysfunction of the RNA-binding protein (RBP), TAR DNA-binding protein 43 (TDP-43). Strikingly, genes and exon junctions affected by TDP-43 knockdown overlapped significantly with those dysregulated across brain regions in PD. In brains from individuals with the LRRK2 c.6055G>A (p.G2019S) mutation, the most common genetic cause of PD, we also observed significant enrichment of TDP-43-dependent splicing changes. This finding was corroborated in human pluripotent stem cell-derived midbrain dopaminergic neurons and a LRRK2 p.G2019S knock-in mouse model, where reduced nuclear TDP-43 levels evidenced the well-recognised loss-of-function mechanism contributing to splicing dysregulation. By leveraging our RNA-based analyses we predicted TDP-43-dependent novel peptide sequences and validated their existence within human LRRK2 mutation mDNs, while also demonstrating an overall loss of protein and mRNA expression in mis-spliced genes. Collectively, our findings reveal that PD is marked by extensive splicing dysregulation dependent on TDP-43, making TDP-43 a promising new therapeutic target in PD.

neuroscience↗

bioRxiv2025

Cellular and Extracellular microRNA Dysregulation in LRRK2-Linked Parkinson's Disease

Background and objectiveThe discovery of cell-free micro-RNAs in body fluids has made them a promising biomarker target in the field of neurodegenerative diseases. Although they have been reported to be differentially expressed in biofluids and tissues from sporadic Parkinsons disease patients, it remains unclear whether similar observations can be made in patients with genetic forms of the disease and if miRNA profiles reflect mutation-specific pathogenic pathways. Since induced pluripotent stem cell-derived neurons represent a widely used research model for both sporadic and familial Parkinsons disease, we sought to assess the usability of this model for the identification of differentially expressed cell-free micro-RNAs in the context of the Parkinsons disease-related LRRK2 G2019S mutation in a proof-of-concept study. Materials and methodsWe isolated extracellular vesicles carrying cell-free RNA from patient-derived induced pluripotent stem cells carrying the LRRK2 G2019S mutation and their gene-corrected isogenic controls. After the generation of small-RNA libraries and differential expression analysis, we quantified expression levels of fourteen micro-RNAs in an independent batch of cell-free and cellular RNA via RT-qPCR. Finally, we quantified pRab10 levels as a proxy of LRRK2 activity and correlated observable changes to the miRNA expression levels. ResultsWe successfully isolated extracellular vesicles from induced pluripotent stem cell-derived human dopaminergic neurons. We detected over 2000 different micro-RNAs of which 56 were differentially expressed. Dysregulation of four micro-RNAs was confirmed in an independent batch of cell-free RNA. We discovered a high correlation between changes in the cell-free and cellular micro-RNAomes. Finally, we showed poor correlation between LRRK2 expression or activity and miRNA expression levels. ConclusionsOur results suggest that patients carrying the LRRK2 G2019S mutation display alterations in cellular and cell-free micro-RNA expression levels. Notably, the miRNA changes observed in this study did not follow a linear relationship with LRRK2 expression levels or kinase activity. Validation in larger cohorts will be necessary.

neuroscience↗