Selective Cochlear Degeneration in Mice Lacking the F-Box Protein, Fbx2, a Glycoprotein-Specific Ubiquitin Ligase Subunit

Rick F. Nelson; Kevin A. Glenn; Yuzhou Zhang; Hsiang Wen; Tina Knutson; Cynthia M. Gouvion; Barbara K. Robinson; Zouping Zhou; Baoli Yang; Richard J.H. Smith; Henry L. Paulson

doi:10.1523/JNEUROSCI.0206-07.2007

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Selective Cochlear Degeneration in Mice Lacking the F-Box Protein, Fbx2, a Glycoprotein-Specific Ubiquitin Ligase Subunit

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Selective Cochlear Degeneration in Mice Lacking the F-Box Protein, Fbx2, a Glycoprotein-Specific Ubiquitin Ligase Subunit

Rick F. Nelson, Kevin A. Glenn, Yuzhou Zhang, Hsiang Wen, Tina Knutson, Cynthia M. Gouvion, Barbara K. Robinson, Zouping Zhou, Baoli Yang, Richard J.H. Smith, …

Journal of Neuroscience, Vol.27(19), pp.5163-5171

05/09/2007

DOI: 10.1523/JNEUROSCI.0206-07.2007

PMCID: PMC6672365

PMID: 17494702

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Abstract

Little is known about the role of protein quality control in the inner ear. We now report selective cochlear degeneration in mice deficient in Fbx2, a ubiquitin ligase F-box protein with specificity for high-mannose glycoproteins (Yoshida et al., 2002). Originally described as a brain-enriched protein (Erhardt et al., 1998), Fbx2 is also highly expressed in the organ of Corti, in which it has been called organ of Corti protein 1 (Thalmann et al., 1997). Mice with targeted deletion of Fbxo2 develop age-related hearing loss beginning at 2 months. Cellular degeneration begins in the epithelial support cells of the organ of Corti and is accompanied by changes in cellular membrane integrity and early increases in connexin 26, a cochlear gap junction protein previously shown to interact with Fbx2 (Henzl et al., 2004). Progressive degeneration includes hair cells and the spiral ganglion, but the brain itself is spared despite widespread CNS expression of Fbx2. Cochlear Fbx2 binds Skp1, the common binding partner for F-box proteins, and is an unusually abundant inner ear protein. Whereas cochlear Skp1 levels fall in parallel with the loss of Fbx2, other components of the canonical SCF (Skp1, Cullin1, F-box, Rbx1) ubiquitin ligase complex remain unchanged and show little if any complex formation with Fbx2/Skp1, suggesting that cochlear Fbx2 and Skp1 form a novel, heterodimeric complex. Our findings demonstrate that components of protein quality control are essential for inner ear homeostasis and implicate Fbx2 and Skp1 as potential genetic modifiers in age-related hearing loss.

Obstetrics and Gynecology

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Title: Subtitle: Selective Cochlear Degeneration in Mice Lacking the F-Box Protein, Fbx2, a Glycoprotein-Specific Ubiquitin Ligase Subunit
Creators: Rick F. Nelson
Kevin A. Glenn
Yuzhou Zhang
Hsiang Wen
Tina Knutson
Cynthia M. Gouvion
Barbara K. Robinson
Zouping Zhou
Baoli Yang - University of Iowa
Richard J.H. Smith
Henry L. Paulson
Resource Type: Journal article
Publication Details: Journal of Neuroscience, Vol.27(19), pp.5163-5171
DOI: 10.1523/JNEUROSCI.0206-07.2007
PMID: 17494702
PMCID: PMC6672365
NLM abbreviation: J Neurosci
ISSN: 0270-6474
eISSN: 1529-2401
Language: English
Date published: 05/09/2007
Academic Unit: Psychiatry; Iowa Neuroscience Institute; Obstetrics and Gynecology; Otolaryngology
Record Identifier: 9983557244202771

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