Proteasome mapping reveals sexual dimorphism in tissue-specific sensitivity to protein aggregations

Authors

Edmund Charles Jenkins, Icahn School of Medicine at Mount Sinai
Nagma Shah, Icahn School of Medicine at Mount Sinai
Maria Gomez, Icahn School of Medicine at Mount Sinai
Gabriella Casalena, Weill Cornell Medicine
Dazhi Zhao, Weill Cornell Medicine
Timothy C. Kenny, Icahn School of Medicine at Mount Sinai
Sara Rose Guariglia, CUNY College of Staten IslandFollow
Giovanni Manfredi, Weill Cornell Medicine
Doris Germain, Icahn School of Medicine at Mount Sinai

Document Type

Article

Publication Date

2-23-2020

Abstract

Defects in the proteasome can result in pathological proteinopathies. However, the pathogenic role of sex- and tissue-specific sensitivity to proteotoxic stress remains elusive. Here, we map the proteasome activity across nine tissues, in male and female mice, and demonstrate strong sexual dimorphism in proteasome activity, where females have significantly higher activity in several tissues. Further, we report drastic differences in proteasome activity among tissues, independently of proteasome concentration, which are exacerbated under stress conditions. Sexual dimorphism in proteasome activity is confirmed in a SOD1ALS mouse model, in which the spinal cord, a tissue with comparatively low proteasome activity, is severely affected. Our results offer mechanistic insight into tissue-specific sensitivities to proteostasis stress and into sex differences in the progression of neurodegenerative proteinopathies.

Comments

This work was originally published in EMBO Reports available at https://doi.org/10.15252/embr.201948978

Published under the terms of the CC BY NC ND 4.0 license.