Dataset Information

Neurodegenerative disease mouse model SDS-insoluble proteins

ABSTRACT: The deposition of pathologic misfolded proteins in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and amyotrophic lateral sclerosis is hypothesized to burden protein homeostatic (proteostatic) machinery, potentially leading to insufficient capacity to maintain the proteome. This hypothesis has been supported by previous work in our laboratory, as evidenced by the perturbation of cytosolic protein solubility in response to amyloid plaques in a mouse model of Alzheimer’s amyloidosis. In the current study, we demonstrate changes in proteome solubility are a common pathology to mouse models of neurodegenerative disease. Pathological accumulations of misfolded tau, α-synuclein and mutant superoxide dismutase 1 in CNS tissues of transgenic mice was associated with changes in the solubility of hundreds of CNS proteins in each model. We observed that changes in proteome solubility were progressive and, using the rTg4510 model of inducible tau pathology, demonstrated that these changes were dependent upon sustained expression of the primary pathologic protein. In all of the models examined, changes in proteome solubility were robust, easily detected, and provided a sensitive indicator of proteostatic disruption. Interestingly, a subset of the proteins that display a shift towards insolubility were common between these different models, suggesting that a specific subset of the proteome is vulnerable to proteostatic disruption. Overall, our data suggest that neurodegenerative proteinopathies modeled in mice impose a burden on the proteostatic network that diminishes the ability of neural cells to prevent aberrant conformational changes that alter the solubility of hundreds of abundant cellular proteins.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Spinal Cord

SUBMITTER: Guilian Xu

LAB HEAD: Guilian Xu

PROVIDER: PXD010828 | Pride | 2018-08-29

REPOSITORIES: Pride

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Publications

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

Pace Michael C MC Xu Guilian G Fromholt Susan S Howard John J Crosby Keith K Giasson Benoit I BI Lewis Jada J Borchelt David R DR

Acta neuropathologica 20180823 6

The deposition of pathologic misfolded proteins in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia and amyotrophic lateral sclerosis is hypothesized to burden protein homeostatic (proteostatic) machinery, potentially leading to insufficient capacity to maintain the proteome. This hypothesis has been supported by previous work in our laboratory, as evidenced by the perturbation of cytosolic protein solubility in response to amyloid plaques in ...[more]

PMID: 30140941

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Project description:A hallmark pathology of Alzheimer’s disease (AD) is the formation of amyloid ß (Aß) 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 Aß 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 Aß peptides, the levels and length of Aß 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 Aß morphology dominates. In prior studies of mice that primarily develop cored-neuritic deposits, we determined that Aß 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 Aß deposit morphologies. We find a surprisingly diverse range of changes in proteome solubility across these models. Mice that deposit human Aß40 and Aß42 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 Aß42 deposits but to a lesser extent. Notably, mice with cored deposits containing only Aß42 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 Aß pathology and support the view that fibrillar cored-neuritic plaque pathology is the more disruptive Aß pathology in the Alzheimer’s cascade.

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Dataset Information

Neurodegenerative disease mouse model SDS-insoluble proteins

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Publications

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

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