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

Sengupta, Urmi; Montalbano, Mauro; McAllen, Salome; Minuesa, Gerard; Kharas, Michael G.; Kayed, Rakez

doi:10.1186/s40478-018-0615-0

Cited by 29 publications

(35 citation statements)

References 56 publications

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“…The filter trap assay was performed using a Bio-Dot SF microfiltration apparatus (Bio-Rad), as described previously ( 48 , 80 , 90 ). Briefly, 1 μg of each end-product reaction was applied onto nitrocellulose membranes, previously prewetted in TBS with very low Tween 0.01% (TBS-T), through the use of a vacuum-based bio-slot apparatus.…”

Section: Methodsmentioning

confidence: 99%

Modulating disease-relevant tau oligomeric strains by small molecules

Cascio

Garcia

Montalbano

et al. 2020

Journal of Biological Chemistry

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The pathological aggregation of tau plays an important role in Alzheimer’s disease (AD) and many other related neurodegenerative diseases, collectively referred to as tauopathies. Recent evidence has demonstrated that tau oligomers, small and soluble prefibrillar aggregates, are highly toxic due to their strong ability to seed tau misfolding and propagate the pathology seen across different neurodegenerative diseases. We previously showed that novel curcumin derivatives affect preformed tau oligomer aggregation pathways by promoting the formation of more aggregated and nontoxic tau aggregates. To further investigate their therapeutic potential, we have extended our studies to disease-relevant brain-derived tau oligomers (BDTOs). Herein, using well-characterized BDTOs, isolated from brain tissues of different tauopathies, including AD, progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB), we found that curcumin derivatives modulate the aggregation state of BDTOs by reshaping them and rescue neurons from BDTOs-associated toxicity. Interestingly, compound CL3 showed an effect on the aggregation pattern of BDTOs from different tauopathies, resulting in the formation of less neurotoxic larger tau aggregates with decreased hydrophobicity and seeding propensity. Our results lay the groundwork for potential investigations of the efficacy and beneficial effects of CL3 and other promising compounds for the treatment of tauopathies. Furthermore, CL3 may aid in the development of tau imaging agent for the detection of tau oligomeric strains and differential diagnosis of the tauopathies, thus enabling earlier interventions.

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Section: Methodsmentioning

confidence: 99%

Modulating disease-relevant tau oligomeric strains by small molecules

Cascio

Garcia

Montalbano

et al. 2020

Journal of Biological Chemistry

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“…Musashi-1 is a particularly interesting RBP. Its roles in mediating stem cell regeneration and cell differentiation are well-known [25], and recent evidence suggests it may be implicated in neurodegenerative diseases [26,27], as have the prominent RBPs TDP-43 and FUS [28,29]. The removal of Musashi-1 s IDR prevents this protein's recruitment to stress granules that reduce the chemoresistance of some types of cancer cells [30,31].…”

Section: Of 14mentioning

confidence: 99%

Musashi-1: An Example of How Polyalanine Tracts Contribute to Self-Association in the Intrinsically Disordered Regions of RNA-Binding Proteins

Chen¹,

Huang²

2020

IJMS

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RNA-binding proteins (RBPs) have intrinsically disordered regions (IDRs) whose biophysical properties have yet to be explored to the same extent as those of the folded RNA interacting domains. These IDRs are essential to the formation of biomolecular condensates, such as stress and RNA granules, but dysregulated assembly can be pathological. Because of their structural heterogeneity, IDRs are best studied by NMR spectroscopy. In this study, we used NMR spectroscopy to investigate the structural propensity and self-association of the IDR of the RBP Musashi-1. We identified two transient α-helical regions (residues ~208–218 and ~270–284 in the IDR, the latter with a polyalanine tract). Strong NMR line broadening in these regions and circular dichroism and micrography data suggest that the two α-helical elements and the hydrophobic residues in between may contribute to the formation of oligomers found in stress granules and implicated in Alzheimer’s disease. Bioinformatics analysis suggests that polyalanine stretches in the IDRs of RBPs may have evolved to promote RBP assembly.

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“…We previously reported that the cellular localization of MSI1 and MSI2 in human AD cortical tissues is found in the cytoplasm and nuclei of mature neurons (Sengupta et al, ). In this scenario, we demonstrated that tau oligomers (TauO) interact with the MSI proteins in AD brains, and that MSI proteins are able to form oligomers in vitro (Sengupta et al, ). Clarifying their cell compartment location and regulation is an important step to identifying MSI’s crucial roles in the pathogenesis of AD.…”

Section: Introductionmentioning

confidence: 99%

Tau oligomers mediate aggregation of RNA‐binding proteins Musashi1 and Musashi2 inducing Lamin alteration

et al. 2019

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The exact mechanisms leading to neurodegeneration in Alzheimer's disease (AD) and other tauopathies are not yet entirely understood. However, it is known that several RNA‐binding proteins (RBPs) form toxic aggregates and also interact with tau in such granules in tauopathies, including AD. The Musashi (MSI) family of RBPs, consisting of two homologues: Musashi1 and Musashi2, have not been extensively investigated in neurodegenerative diseases. Here, using a tau inducible HEK (iHEK) model we investigate whether MSI proteins contribute to the aggregation of toxic tau oligomers (TauO). Wild‐type and mutant P301L tau iHEK cells are used to study the effect of different tau variants on the cellular localization of MSI proteins. Interestingly, we observe that tau co‐localizes with MSI in the cytoplasm and nuclei, altering the nuclear transport of MSI. Furthermore, incremental changes in the size and density of nuclear MSI/tau foci are observed. We also report here that TauO interact with MSI to cause the formation of distinct nuclear aggregates. Moreover, tau/MSI aggregates induce structural changes to LaminB1, leading to nuclear instability. These results illustrate a possible mechanism of neurodegeneration mediated by the aggregation of MSI proteins and TauO, suggesting that MSI plays a critical role in cellular dysfunction.

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

Cited by 29 publications

References 56 publications

Modulating disease-relevant tau oligomeric strains by small molecules

Modulating disease-relevant tau oligomeric strains by small molecules

Musashi-1: An Example of How Polyalanine Tracts Contribute to Self-Association in the Intrinsically Disordered Regions of RNA-Binding Proteins

Tau oligomers mediate aggregation of RNA‐binding proteins Musashi1 and Musashi2 inducing Lamin alteration

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