title: Intrasarcoplasmic amyloidosis impairs proteolytic function of proteasomes in cardiomyocytes by compromising substrate uptake.
abstract: The presence of increased ubiquitinated proteins and amyloid oligomers in failing human hearts strikingly resembles the characteristic pathology in the brain of many neurodegenerative diseases. The ubiquitin-proteasome system (UPS) is responsible for degradation of most cellular proteins and plays essential roles in virtually all cellular processes. UPS impairment by aberrant protein aggregation was previously shown in cell culture but remains to be demonstrated in intact animals. Mechanisms underlying the impairment are poorly understood. We report here that UPS proteolytic function is severely impaired in the heart of a mouse model of intrasarcoplasmic amyloidosis caused by cardiac-restricted expression of a human desmin-related myopathy-linked missense mutation of alphaB-crystallin (CryAB(R120G)). The UPS impairment was detected before cardiac hypertrophy, and failure became discernible, suggesting that defective protein turnover likely contributes to cardiac remodeling and failure in this model. Further analyses reveal that the impairment is likely attributable to insufficient delivery of substrate proteins into the 20S proteasomes, and depletion of key components of the 19S subcomplex may be responsible. The derangement is likely caused by aberrant protein aggregation rather than loss of function of the CryAB gene because UPS malfunction was not evident in CryAB-null hearts and inhibition of aberrant protein aggregation by Congo red or a heat shock protein significantly attenuated CryAB(R120G)-induced UPS malfunction in cultured cardiomyocytes. Because of the central role of the UPS in cell regulation and the high intrasarcoplasmic amyloidosis prevalence in failing human hearts, our data suggest a novel pathogenic process in cardiac disorders with abnormal protein aggregation.
authors.affiliation: Cardiovascular Research Institute, South Dakota Health Research Foundation, University of South Dakota School of Medicine, Sioux Valley Hospitals and Health System, Sioux Falls, SD, USA.
authors.forename: Quanhai
authors.initials: Q
authors.lastname: Chen
authors.forename: Jin-Bao
authors.initials: JB
authors.lastname: Liu
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Horak
authors.forename: Hanqiao
authors.initials: H
authors.lastname: Zheng
authors.forename: Asangi R K
authors.initials: AR
authors.lastname: Kumarapeli
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Faqian
authors.initials: F
authors.lastname: Li
authors.forename: A Martin
authors.initials: AM
authors.lastname: Gerdes
authors.forename: Eric F
authors.initials: EF
authors.lastname: Wawrousek
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
mesh_terms: D000686:Amyloidosis / Q000378:metabolism*; D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology; D003893:Desmin / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006333:Heart Failure / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D020257:Ventricular Remodeling; D038205:beta-Crystallin A Chain / Q000235:genetics
chemical_list: D003893:Desmin; D011506:Proteins; D025801:Ubiquitin; D038205:beta-Crystallin A Chain; D046988:Proteasome Endopeptidase Complex