Changes in proteome solubility indicate widespread proteostatic disruption in mouse models of neurodegenerative disease

Pace, Michael C.; Xu, Guilian; Fromholt, Susan; Howard, John; Crosby, Keith; Giasson, Benoit I.; Lewis, Jada; Borchelt, David R.

doi:10.1007/s00401-018-1895-y

Cited by 27 publications

(34 citation statements)

References 105 publications

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“…3, 4). As expected based on our previous results [34], synthesis of many proteins was suppressed by tau expression; however, we also identified many proteins that were increased as a consequence of tau expression, which corroborates results that were recently described [41]. Strikingly, transcript levels coding for ribosomal genes were unchanged while the protein levels were rescued by tau suppression, supporting the hypothesis that a shift in translation occurs during the window where doxycycline treatment rescues cognitive impairment in these mice.…”

Section: Discussionsupporting

confidence: 93%

Tau drives translational selectivity by interacting with ribosomal proteins

et al. 2019

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There is a fundamental gap in understanding the consequences of tau–ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. First, we performed microarrays and nascent proteomics to measure changes in protein synthesis. Using regulatable rTg4510 tau transgenic mice, we determined that tau expression differentially shifts both the transcriptome and the nascent proteome, and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and found that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6), a crucial regulator of translation. Consequently, protein synthesis under translational control of rpS6 was reduced under tauopathic conditions in Alzheimer’s disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, since regulation of protein synthesis is critical for learning and memory, aberrant tau–ribosome interactions in disease could explain the linkage between tauopathies and cognitive impairment.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-01970-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

Tau drives translational selectivity by interacting with ribosomal proteins

et al. 2019

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“…Instead, there is a wider metastable subproteome that underlies specific pathological responses to different stresses. These findings complement those of a recent large-scale proteomic study that identified a small number of endogenous proteins that are prone to aggregation in mouse models of different neurodegenerative diseases, including AD, PD and ALS, indicating the presence of metastable subproteome (80). We also note that our results are compatible with the possibility that aggregation occurs more non-specifically if protein folding is generally perturbed.…”

Section: Discussionsupporting

confidence: 90%

Widespread remodelling of proteome solubility in response to different protein homeostasis stresses

Sui

Pires

Nie

et al. 2019

Preprint

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The accumulation of protein deposits in neurodegenerative diseases involves the presence of a metastable subproteome vulnerable to aggregation. To investigate this subproteome and the mechanisms that regulates it, we measured the proteome solubility of the Neuro2a cell line under protein homeostasis stresses induced by Huntington Disease proteotoxicity; Hsp70, Hsp90, proteasome and ERmediated folding inhibition; and oxidative stress. We found one-quarter of the proteome extensively changed solubility. Remarkably, almost all the increases in insolubility were counteracted by increases in solubility of other proteins. Each stress directed a highly specific pattern of change, which reflected the remodelling of protein complexes involved in adaptation to perturbation, most notably stress granule proteins, which responded differently to different stresses. These results indicate that the robustness of protein homeostasis relies on the absence of proteins highly vulnerable to aggregation and on large changes in aggregation state of regulatory mechanisms that restore protein solubility upon specific perturbations.2

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“…The pellets were suspended in Laemmeli buffer [21] and stored as the SDS-P fractions. As in previous work using LC-MS/MS, the primary comparison was between PBS soluble fractions (PBS-S) and SDS insoluble fractions (SDS-P) to identify proteins that are normally readily detectable in soluble fractions but became over-represented in insoluble fractions in mice with Aβ pathology [34,42].…”

Section: Protein Identification By Lc-ms/msmentioning

confidence: 99%

“…In prior studies of the APPswe/PS1dE9 model of Alzheimer-type amyloidosis, we observed age-dependent changes in the solubility of the proteome such that cytosolic brain proteins became over-represented in SDSinsoluble extracts [34,42]. A subset of the proteins identified in the APPswe/PS1dE9 model were also identified as losing solubility in mice that model neurofibrillary tangle (NFT) pathology, superoxide dismutase 1 (SOD1) pathology, and α-synuclein pathology [34].…”

Section: Introductionmentioning

confidence: 99%

“…A subset of the proteins identified in the APPswe/PS1dE9 model were also identified as losing solubility in mice that model neurofibrillary tangle (NFT) pathology, superoxide dismutase 1 (SOD1) pathology, and α-synuclein pathology [34]. Importantly, it did not appear that the changes in solubility of any one protein were sufficient to lower function, leading us to view the observed changes in protein solubility as a biomarker of general proteostasis dysfunction [34]. The proteins we identify as insoluble may be the result of reduced capacity to fold newly-made proteins or to lowered efficiency in degrading proteins that have failed to achieve native conformations [40].…”

Section: Introductionmentioning

confidence: 99%

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Diversity in Aβ deposit morphology and secondary proteome insolubility across models of Alzheimer-type amyloidosis

Fromholt

Chakrabarty

et al. 2020

acta neuropathol commun

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A hallmark pathology of Alzheimer's disease (AD) is the formation of amyloid β (Aβ) deposits that exhibit diverse localization and morphologies, ranging from diffuse to cored-neuritic deposits in brain parenchyma, with cerebral vascular deposition in leptomeningeal and parenchymal compartments. Most AD brains exhibit the full spectrum of pathologic Aβ morphologies. In the course of studies to model AD amyloidosis, we have generated multiple transgenic mouse models that vary in the nature of the transgene constructs that are expressed; including the species origin of Aβ peptides, the levels and length of Aβ that is deposited, and whether mutant presenilin 1 (PS1) is co-expressed. These models recapitulate features of human AD amyloidosis, but interestingly some models can produce pathology in which one type of Aβ morphology dominates. In prior studies of mice that primarily develop cored-neuritic deposits, we determined that Aβ deposition is associated with changes in cytosolic protein solubility in which a subset of proteins become detergent-insoluble, indicative of secondary proteome instability. Here, we survey changes in cytosolic protein solubility across seven different transgenic mouse models that exhibit a range of Aβ deposit morphologies. We find a surprisingly diverse range of changes in proteome solubility across these models. Mice that deposit human Aβ40 and Aβ42 in cored-neuritic plaques had the most robust changes in proteome solubility. Insoluble cytosolic proteins were also detected in the brains of mice that develop diffuse Aβ42 deposits but to a lesser extent. Notably, mice with cored deposits containing only Aβ42 had relatively few proteins that became detergent-insoluble. Our data provide new insight into the diversity of biological effects that can be attributed to different types of Aβ pathology and support the view that fibrillar cored-neuritic plaque pathology is the more disruptive Aβ pathology in the Alzheimer's cascade.

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Changes in proteome solubility indicate widespread proteostatic disruption in mouse models of neurodegenerative disease

Cited by 27 publications

References 105 publications

Tau drives translational selectivity by interacting with ribosomal proteins

Tau drives translational selectivity by interacting with ribosomal proteins

Widespread remodelling of proteome solubility in response to different protein homeostasis stresses

Diversity in Aβ deposit morphology and secondary proteome insolubility across models of Alzheimer-type amyloidosis

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