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Formation of Toxic Oligomeric Assemblies of RNA-binding Protein: Musashi in Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with structural and functional alterations of brain cells causing progressive deterioration of memory and other cognitive functions. Recent studies demonstrate that several neurodegenerative diseases, including AD exhibit RNA-binding proteins (RBPs) pathologies, including TAR DNA -binding protein (TDP-43), fused in sarcoma (FUS), superoxide dismutase (SOD1) and T-interacting antigen-1 (TIA-1), highlighting the role of RBPs in neurodegeneration. One such group of RBPs, Musashi proteins comprised of MSI1 and MSI2, has been long studied in neurogenesis and cancer biology. Herein, we have investigated the aggregation properties of MSI1 and MSI2 by in vitro assays, their expression and accumulation as well as their possible interactions with other cellular proteins, such as tau in AD pathology. We have performed atomic force microscopy, Western blot, and immunoprecipitation to demonstrate the aggregation properties of recombinant Musashi proteins. Furthermore, we have studied cortical brain sections from AD (N = 4) and age-matched non-demented subjects (N = 4) by Western blot and immunofluorescence microscopy to investigate MSI1 and MSI2 levels and their localization in human brain tissues. Musashi proteins showed in vitro aggregation properties by forming oligomers. We have observed an increase in Musashi proteins levels in AD brain tissues as compared with age-matched non-demented subjects. Moreover, Musashi proteins are observed to form oligomers in the diseased brain tissues. Interestingly, the co-immunofluorescence study has revealed a change in fluorescence pattern of oligomeric Musashi proteins and tau with a high association in the perinuclear area of the cells suggesting changes in function of Musashi proteins. Our data have demonstrated for the first time that MSI1 and MSI2 are present in an oligomeric state in AD brains compared to the age-matched non-demented subjects and that these large assemblies co-localize with tau contributing to the neurodegenerative pathogenesis.

SUBMITTER: Sengupta U

PROVIDER: S-EPMC6203984 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. Although much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act posttranscriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBP) Musashi-1 (MSI1) and Musashi-2 (MSI2) are emerging as regulators of multiple critical biological processes relevant to cancer initiation, progression, and drug resistance. Following identification of Musashi as a regulator of progenitor cell identity in Drosophila, the human Musashi proteins were initially linked to control of maintenance of hematopoietic stem cells, then stem cell compartments for additional cell types. More recently, the Musashi proteins were found to be overexpressed and prognostic of outcome in numerous cancer types, including colorectal, lung, and pancreatic cancers; glioblastoma; and several leukemias. MSI1 and MSI2 bind and regulate the mRNA stability and translation of proteins operating in essential oncogenic signaling pathways, including NUMB/Notch, PTEN/mTOR, TGFβ/SMAD3, MYC, cMET, and others. On the basis of these activities, MSI proteins maintain cancer stem cell populations and regulate cancer invasion, metastasis, and development of more aggressive cancer phenotypes, including drug resistance. Although RBPs are viewed as difficult therapeutic targets, initial efforts to develop MSI-specific inhibitors are promising, and RNA interference-based approaches to inhibiting these proteins have had promising outcomes in preclinical studies. In the interim, understanding the function of these translational regulators may yield insight into the relationship between mRNA expression and protein expression in tumors, guiding tumor-profiling analysis. This review provides a current overview of Musashi as a cancer driver and novel therapeutic target. Clin Cancer Res; 23(9); 2143-53. ©2017 AACR.

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Formation of Toxic Oligomeric Assemblies of RNA-binding Protein: Musashi in Alzheimer's disease.

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