- Open Access
Formation of Toxic Oligomeric Assemblies of RNA-binding Protein: Musashi in Alzheimer’s disease
© The Author(s). 2018
- Received: 10 October 2018
- Accepted: 10 October 2018
- Published: 26 October 2018
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.
- Musashi proteins
- Alzheimer’s disease
Herein, we sought to investigate whether the Musashi family members, MSI1 and MSI2 proteins can form aggregates in disease pathology. We observed for the first time in vitro and in ex vivo human AD brains, that these two RBPs are present in their soluble aggregated, i.e., oligomeric forms. These oligomers have been detected in mature neurons that furthermore, co-localize with oligomeric tau. Interestingly, we also observed a change in the patterns of Musashi protein signal, representing cellular distribution of these proteins depending on their association with tau protein. Our observations here suggest that Musashi proteins may have altered cellular localization and possibly dysregulated functions in AD brains, thus contributing to the deleterious effects of aggregated tau.
Preparation of Musashi oligomers
Recombinantly expressed and purified Glutathione-S-transferase (GST)-tagged Musashi proteins. Proteins were then aggregated following our standard protocol . Briefly, both purified MSI1 and MSI2 proteins (0.5 μg/μl) were stirred at 500 RPM with a Teflon-coated micro stir bars for 48 h inside the fume hood at room temperature closed with a cap. MSI1 and MSI2 oligomers were injected into a Shimadzu HPLC system fitted with a TSK-GEL G3000 SWXL (30 cm × 7.8 mm) column, Supelco-808,541. PBS (pH 7.4) was used as the mobile phase with a flow rate of 0.5 mL/min. A gel filtration standard (Bio-Rad 51–1901) was used for calibrations.
Brain tissues analyzed in this study from AD and age-matched non-demented control subjects are summarized
Glutathione (GSH) Agarose beads slurry (50%, Pierce) were centrifuged at 1000 x g to discard the storage buffer. Beads were then washed with wash buffer (1X PBS) two times. MSI1 and MSI2 proteins are separately mixed with tau protein at equimolar ratios and incubated with the washed GSH beads on an end-over-end rotator for 4 h at 4 °C. After washing the beads two times with wash buffer, GST-tagged Musashi proteins were eluted with elution buffer (50 mM Tris, 150 mM NaCl, pH 8.0 containing 10 mM reduced glutathione).
Western blot analysis
Western blot analyses were performed with both recombinant Musashi proteins and homogenates from AD and age-matched control brain tissues. Approximately 4 μg of Musashi oligomeric preparations and 10 μg of each brain homogenate were loaded on precast NuPAGE 4–12% Bis-Tris gels (Invitrogen) for SDS-PAGE analyses. Gels were subsequently transferred onto nitrocellulose membranes and blocked overnight at 4 °C with 10% nonfat dry milk. Membranes were then probed for 1 h at room temperature with α-Oligomeric antibody F11G3 (1:1000), α-MSI1 (1:1000, Abcam), α-MSI2 (1:1000, Abcam) and Tau13 (1:10,000, BioLegend), GAPDH (1:1000, Sigma) antibodies diluted in 5% nonfat dry milk. α-Oligomeric antibody F11G3, α- MSI1 and α- MSI2 immunoreactivity were detected with an HRP-conjugated anti-rabbit IgG (1:6000, GE Healthcare). Tau13 and GAPDH immunoreactivity were detected using an anti-mouse IgG (1:6000, GE Healthcare) diluted in 5% milk. ECL plus (GE Healthcare) was used to visualize the bands.
Filter trap assay
Approximately 15 μg of brain homogenate from each AD and control case (soluble fractions) was applied onto pre-soaked (TBS-T) nitrocellulose membranes, using a vacuum based bioslot apparatus [17, 35, 53]. After blocking with 10% non-fat dry milk solution, membranes were probed with Tau 13 (1:10,000), α- MSI1 (1:1000) and α- MSI2 (1:1000) antibodies diluted in 5% nonfat milk for 1 h at RT. Immunoreactivity of Tau 13, α-MSI1 and α-MSI2 were detected using an HRP-conjugated anti-mouse IgG (1:6000, GE Healthcare) and an HRP-conjugated anti-rabbit IgG (1:6000, GE Healthcare), respectively.
Immunofluorescence and confocal microscopy
Immunofluorescence assays were performed with paraffin and frozen sections of frontal cortices from Alzheimer’s disease and control brains. Paraffin sections were deparafinized and rehydrated whereas, frozen sections were fixed in chilled methanol followed by blocking in 5% normal goat serum blocking for 1 h. Sections were then incubated overnight with F11G3 (1:350), Tau5 (1:300, BioLegend), T22 (1:200), α- MSI (1:250), α- MSI2 (1:250) at 4 °C. After washing three times with PBS (10 mins each), sections were then incubated with goat anti-mouse IgG Alexa- 488 and anti-rabbit Alexa 568 (1:700, Thermo Fisher Scientific), as appropriate, for 1 h. They were then washed and mounted with vectashield® mounting medium with DAPI (Vector Laboratories).
Atomic force microscopy
Oligomeric preparations of both MSI1 and MSI2 proteins were imaged via AFM by ScanAsyst mode with Multimode 8 AFM machine (Bruker, Billerica MA). Briefly, 5 μl of each sample were applied onto a freshly-cleaved mica surface and allowed to adsorb. Mica was then washed with 200 μl of deionized water and air-dried.
The slides were imaged with an epifluorescence microscope (Nikon Eclipse 800) equipped with a CoolSnap-FX monochrome CCD camera (Photometrics) using standard Nikon GFP, FITC and DAPI filters. Images were processed and analyzed with ImageJ (National Institute of Health, NIH). Confocal microscope (Zeiss LSM 880) has been used to obtain the stacks of brain sections with Nikon 40X objective. Z-Stacks (0.5 μm step size) were used for orthogonal representations. All the colocalization Pearson Correlation Co-effcient (PCC), Scatter plots and Profile plots, presented in this manuscript, have been produced using ImageJ Software (NIH).
All raw data were obtained from Western blot and immunofluorescence quantifications. Statistical analyses of these data were performed, using GraphPad prism 6 software. Integrated densities of quantified signals from Western blot analysis and filter trap assay were plotted as bar graphs, expressed as mean ± standard deviation (SD) for AD and age-matched control brain tissues (N = 4, for each group). One-way ANOVA was used to study the occurrence of Musashi proteins in AD cases compared to the control group. To measure the co-localization between Musashi and tau proteins in AD cases, we used Pearson Correlation coefficient (PCC). From each AD brain section, we analyzed 5 ROIs, thus studying 15 ROIs from each case (n = 15, ROIs), separately. A representative analysis of such 15 ROIs from a single AD case is provided here. A cut-off value of 0.05 was considered significant for statistical analyses.
Formation of recombinant Musashi aggregates in-vitro
Presence of Musashi aggregates in AD brain
Distinct cytoplasmic patterns of MSI2 oligomers in AD brain
Neuronal MSI2 oligomers in AD brain
Co-localization of Musashi proteins with tau and its oligomeric forms in AD brain
Over the past decades, RBPs, their dysregulation and toxic roles in neurodegenerative diseases are being actively investigated. Aggregation of many RBPs, such as TIA-1 , FUS, TDP43, hnRNPA1 and hnRNPA2 in Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) proteinopathies are mediated by prion-related domain (PRD) [29, 39]. RBPs also possess RNA-Recognition Motifs (RRMs) by which they interact with RNA molecules. These motifs are found to be conserved for each protein. Apart from such conserved RRMs, the RBPs also possess a glycine-rich domain that is also conserved. This glycine-rich domain is hydrophobic in nature, allowing the reversible aggregation of these proteins as shown with FUS and TDP-43. These two RBPs are strongly implicated in neurodegenerative diseases, such as ALS and AD [16, 23]. Although they are nuclear proteins, cytoplasmic localization of these proteins is noted in stress granules containing aggregates. Apart from AD, the pathological inclusions of tau protein also characterize a group of neurodegenerative diseases, collectively known as tauopathies . Interactions between tau and other RBPs have been demonstrated in neurodegenerative diseases. The Musashi proteins, another group of RBPs are mostly studied to play roles during neurogenesis . There is only one study that had demonstrated the existence of MSI1 protein in neurons bearing tau inclusions in AD and PiD pathologies . However, the occurrence of MSI2 protein and their toxic form of aggregation, i.e., oligomers have not been investigated yet in neurodegeneration. To the best of our knowledge, this is the first study demonstrating Musashi proteins’ aggregation state, specifically the oligomers in AD pathophysiology and their co-occurrence with tau oligomers. We have demonstrated that recombinant MSI1 and MSI2 proteins can be aggregated in vitro as shown for other amyloidogenic proteins, following our published protocol .
We thank the members of the Kayed lab for their support and help.
This work was supported by grants from National Institute of Health AG054025, NS094557 and AG055771 (R.K.), the Gillson Longenbaugh Foundation and the Mitchell Center for Neurodegenerative Disease.
Availability of data and materials
The datasets used and/or analyzed in this current study are available from the corresponding author.
US, MM and RK analyzed and interpreted the results. US and MM performed the staining and imaging. SM performed biochemical experiments. GM and MK provided the recombinant purified Musashi proteins. US, MM and RK wrote the manuscript. US and MM contributed equally. All authors read and approved the manuscript.
The authors declare that they have no competing interests.
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