Understanding The Role Of Stress Granules Sgs In The Pathophysiology Of Principle Neurodegenerative Diseases Als Ad Ftd Frontotemporal Dementia

Download or read book Understanding the Role of Stress Granules (SGs) in the Pathophysiology of Principle Neurodegenerative Diseases: ALS, AD & FTD (Frontotemporal Dementia). written by Dr. Hakim Saboowala and published by Dr.Hakim Saboowala. This book was released on 2020-02-27 with total page 83 pages. Available in PDF, EPUB and Kindle. Book excerpt: For years, the pathological processes contributing to the accumulation of aggregates in neurological diseases were thought to result mainly from non-physiological aggregation of proteins prone to misfolding, which then accumulated because of progressive, age-related deficits in the proteostatic systems, including the proteasomal and autophagic systems. Recent advances suggest that the response that RNA metabolism plays in stress has an important role in the pathophysiology of neurodegenerative diseases, particularly: · Amyotrophic lateral sclerosis, · Frontotemporal dementias and · Alzheimer disease. RNA-binding proteins (RBPs) control the utilization of mRNA during stress, in part through the formation of membrane-less organelles termed stress granules (SGs). These structures form through a process of liquid–liquid phase separation. Major signaling pathways regulating SG formation include the mammalian target of rapamycin (mTOR)–eukaryotic translation initiation factor 4F (eIF4F) and eIF2α pathways, whereas pathways regulating SG dispersion and removal are mediated by valosin-containing protein and the autolysosomal cascade. Post-translational modifications of RBPs also strongly contribute to the regulation of SGs. Evidence indicates that SGs are supposed to be transient structures, but the chronic stresses associated with ageing lead to chronic persistent SGs that appear to act as a nidus for the aggregation of disease-related proteins. Thus a model is suggested describing how intrinsic vulnerabilities within cellular RNA metabolism might lead to the pathological aggregation of RBPs when SGs become persistent. This process might accelerate the pathophysiology of many neurodegenerative diseases and myopathies, and suggests new targets for disease intervention. An attempt has been made as usual in this Booklet to cover the biology of SGs and related translational stress responses and presents a model for how dysfunction of these pathways contributes to many neurodegenerative diseases. It is also attempted to review the emerging biology of LLPS and membrane-less organelles and show how the fundamental biology of these processes renders RBPs (and other nucleotide-binding proteins) prone to aggregation and subsequent neurodegenerative responses. …Dr. H. K. Saboowala. M.B.(Bom) .M.R.S.H.(London)