Nagar, P. | Search bioRxiv

bioRxiv2024

Beyond the Sin3/HDAC Complex: FAM60A emerges as a regulator of RNA Splicing

FAM60A, traditionally linked to chromatin remodeling within the Sin3/HDAC complex, has emerged as a critical regulator in RNA splicing. Employing an integrative approach that combines immunological assays, CRISPR/Cas9 technology, comprehensive genomics, proteomics, and advanced cross-linking mass spectrometry, complemented by sophisticated 3D molecular modeling, our study challenges and extends the existing understanding of FAM60As functional dynamics. Contravening previous perceptions, our findings elucidate that FAM60A does not interact directly with SIN3A, rather establishes direct interactions with SAP30 and HDAC1, redefining its relationship with the Sin3/HDAC complex. These interactions, deciphered through detailed 3D structural analysis supported by cross-linking constraints, signify a complex architectural role of FAM60A within chromatin remodeling processes. Moreover, our research unveils FAM60As pivotal role in RNA processing, particularly in splicing regulation. Through extensive molecular interactions with a diverse array of mRNA-binding proteins and principal spliceosome components, FAM60A emerges as a key regulator of RNA splicing. This expanded role delineates its influence on gene expression regulation, spotlighting its capacity to modulate critical cellular processes. In sum, this study unveils FAM60As key role in gene regulation and RNA splicing, and suggests new paths for cellular and therapeutic research.

molecular biology↗

bioRxiv2023

Sida cordifolia, a medicinal plant is efficacious in models of Huntingtons disease, by reducing ER stress

Background and aimHuntingtons Disease is a severe neurodegenerative disorder caused by misfolded mutant huntingtin proteins with expanded stretches of polyglutamines aggregating and destroying cells in the nervous system. Sida cordifolia and Acorus calamus are medicinal plants used in traditional Ayurvedic medicine to treat neurological disorders. Here, we tested the effectiveness of extracts of both medicinal plants in decreasing aggregation of mutant huntingtin protein in models of Huntingtons Disease and explored the mode of action. Experimental procedureWe used two models, the nematode Caenorhabditis elegans and a transgenic mouse neuroblastoma cell line, both expressing mutant huntingtin proteins with elongated polyglutamines. We assessed the effect of Sida cordifolia and Acorus calamus on mutant huntingtin protein aggregation in both models, and additionally used the cell line for mechanistic studies to identify cellular pathways underlying the effects of treatment. Results and conclusionHere, we show that an extract of Sida cordifolia inhibits aggregation of mutant huntingtin proteins. In the C. elegans model, the extract prolonged life span and improved motility of the nematode by reducing aggregation of the mutant huntingtin protein. Acorus calamus did not exhibit these effects. In the transgenic mouse neuroblastoma cell line, the extract decreased aggregation of the mutant huntingtin protein by suppressing key pathways in the ER stress response caused by the mutant protein. Our results highlight the potential therapeutic value of Sida cordifolia and its promise as a source for novel medications. HighlightsO_LISida cordifolia extract reduces aggregates in HD model of transgenic worms C_LIO_LIReduction in aggregates leads to improved motility and longevity C_LIO_LISida cordifolia extract reduces ER stress in cells expressing mHTT protein C_LIO_LIFirst report on the pharmacology of Sida cordifolia in neurodegeneration C_LI

pharmacology and toxicology↗