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

Acta Neuropathologica
Michael C PaceDavid R Borchelt

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 were 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 indica...Continue Reading

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Citations

Feb 14, 2019·Acta Neuropathologica·Shon A KorenJose F Abisambra
Oct 12, 2019·International Journal of Molecular Sciences·Anastasiia BohushAnna Filipek
Jun 5, 2020·Quarterly Reviews of Biophysics·Tessa SinnigeMichele Vendruscolo
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Apr 20, 2019·International Journal of Molecular Sciences·Salinee JantrapiromMasamitsu Yamaguchi
Jun 21, 2020·Alzheimer's Research & Therapy·Devin KepchiaDavid Schubert
Feb 4, 2021·International Journal of Molecular Sciences·Shon A KorenJose F Abisambra
May 1, 2020·Trends in Neurosciences·Justin J YerburyLuke McAlary
Apr 20, 2021·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Xiaohang LiDietmar Rudolf Thal
Apr 13, 2021·Molecular & Cellular Proteomics : MCP·Maxwell C McCabeKirk C Hansen

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