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

ABSTRACT: 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.

SUBMITTER: Montalbano M

PROVIDER: S-EPMC6826126 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Montalbano Mauro M McAllen Salome S Sengupta Urmi U Puangmalai Nicha N Bhatt Nemil N Ellsworth Anna A Kayed Rakez R

Aging cell 20190918 6

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 inve ...[more]

PMID: 31532069

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Project description:Neurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease-specific 'seed' proteins; however, roles of other co-aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control-subject pools using magnetic-bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high-resolution proteomics. Although total detergent-insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or A?1-42 pulldown, the protein constituents of Alzheimer-derived aggregates were more abundant, diverse, and post-translationally modified than those from controls. Tau- and A?-containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer-specific protein enrichment in tau-containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co-aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co-localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer-specific enrichment in tau-containing aggregates, were assessed for aggregation-promoting roles in C. elegans by RNA-interference 'knockdown'. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle A?, and 12 (57%) rescued chemotaxis disrupted by neuronal A? expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by A?1-42 . These observations imply shared mechanisms driving both types of aggregation, and/or aggregate-mediated cross-talk between tau and A?. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

Dataset Information

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

Publications

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

Similar Datasets

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