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

AbstractThe 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 lab oratory, 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. Pathologica l 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 o f 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. Interestin gly, 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 proteost...

Source: Acta Neuropathologica - August 23, 2018 Category: Neurology Source Type: research