Muscle Histopathological Abnormalities in a Patient With a CCT5 Mutation Predicted to Affect the Apical Domain of the Chaperonin Subunit

Frontiers in Molecular Biosciences

Kathryn H. Myburgh¹  Mario Giuffrè²  Giampaolo Barone³  Francesca Rappa⁴  Antonella Marino Gammazza⁴  Giuseppe Donato Mangano⁴  Rosario Barone⁴  Francesco Cappello⁴  Vincenzo Antona⁵  Giosuè Lo Bosco⁶  Domenico Amato⁶  Everly Conway de Macario⁸  Giusy Sentiero⁹  Alberto J. L. Macario⁹  Federica Scalia⁹  Maria Vadalà⁹  Alessandra Maria Vitale⁹  Fabrizio Lo Celso^1,10  Filippo Macaluso^1,11 

[1] Technologies (SMARTEST) Research Center, eCampus University, Palermo, Italy;0Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD, United States;Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy;Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, Palermo, Italy;Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy;Department of Mathematics and Computer Science, University of Palermo, Palermo, Italy;Department of Physics and Chemistry - Emilio Segrè, University of Palermo, Palermo, Italy;Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa;Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy;Ionic Liquids Laboratory, Institute of Structure of Matter, Italian National Research Council (ISM-CNR), Rome, Italy;;SMART Engineering Solutions &

关键词: CCT5;    neurochaperonopathies;    chaperonin;    neurodegenerative diseases;    neuropathies;    chaperone system;   

DOI  :  10.3389/fmolb.2022.887336

来源: DOAJ

【 摘 要 】

Recognition of diseases associated with mutations of the chaperone system genes, e.g., chaperonopathies, is on the rise. Hereditary and clinical aspects are established, but the impact of the mutation on the chaperone molecule and the mechanisms underpinning the tissue abnormalities are not. Here, histological features of skeletal muscle from a patient with a severe, early onset, distal motor neuropathy, carrying a mutation on the CCT5 subunit (MUT) were examined in comparison with normal muscle (CTR). The MUT muscle was considerably modified; atrophy of fibers and disruption of the tissue architecture were prominent, with many fibers in apoptosis. CCT5 was diversely present in the sarcolemma, cytoplasm, and nuclei in MUT and in CTR and was also in the extracellular space; it colocalized with CCT1. In MUT, the signal of myosin appeared slightly increased, and actin slightly decreased as compared with CTR. Desmin was considerably delocalized in MUT, appearing with abnormal patterns and in precipitates. Alpha-B-crystallin and Hsp90 occurred at lower signals in MUT than in CTR muscle, appearing also in precipitates with desmin. The abnormal features in MUT may be the consequence of inactivity, malnutrition, denervation, and failure of protein homeostasis. The latter could be at least in part caused by malfunction of the CCT complex with the mutant CCT5 subunit. This is suggested by the results of the in silico analyses of the mutant CCT5 molecule, which revealed various abnormalities when compared with the wild-type counterpart, mostly affecting the apical domain and potentially impairing chaperoning functions. Thus, analysis of mutated CCT5 in vitro and in vivo is anticipated to provide additional insights on subunit involvement in neuromuscular disorders.

【 授权许可】

Unknown