Biomedical subjects

Chantal M Longo-Guess

Publications and source records attributed to Chantal M Longo-Guess.

5 recordsLinked to original sources

PubMed2006

The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function.

Although CLIC5 is a member of the chloride intracellular channel protein family, its association with actin-based cytoskeletal structures suggests that it may play an important role in their assembly or maintenance. Mice homozygous for a new spontaneous recessive mutation of the Clic5 gene, named jitterbug (jbg), exhibit impaired hearing and vestibular dysfunction. The jbg mutation is a 97 bp intragenic deletion that causes skipping of exon 5, which creates a translational frame shift and premature stop codon. Western blot and immunohistochemistry results confirmed the predicted absence of CLIC5 protein in tissues of jbg/jbg mutant mice. Histological analysis of mutant inner ears revealed dysmorphic stereocilia and progressive hair cell degeneration. In wild-type mice, CLIC5-specific immunofluorescence was detected in stereocilia of both cochlear and vestibular hair cells and also along the apical surface of Kolliker's organ during cochlear development. Refined immunolocalization in rat and chicken vestibular hair cells showed that CLIC5 is limited to the basal region of the hair bundle, similar to the known location of radixin. Radixin immunostaining appeared reduced in hair bundles of jbg mutant mice. By mass spectrometry and immunoblotting, CLIC5 was shown to be expressed at high levels in stereocilia of the chicken utricle, in an approximate 1:1 molar ratio with radixin. These results suggest that CLIC5 associates with radixin in hair cell stereocilia and may help form or stabilize connections between the plasma membrane and the filamentous actin core.

Acoustic Stimulation↗

PubMed2006

Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration.

Misfolded proteins are associated with several pathological conditions including neurodegeneration. Although some of these abnormally folded proteins result from mutations in genes encoding disease-associated proteins (for example, repeat-expansion diseases), more general mechanisms that lead to misfolded proteins in neurons remain largely unknown. Here we demonstrate that low levels of mischarged transfer RNAs (tRNAs) can lead to an intracellular accumulation of misfolded proteins in neurons. These accumulations are accompanied by upregulation of cytoplasmic protein chaperones and by induction of the unfolded protein response. We report that the mouse sticky mutation, which causes cerebellar Purkinje cell loss and ataxia, is a missense mutation in the editing domain of the alanyl-tRNA synthetase gene that compromises the proofreading activity of this enzyme during aminoacylation of tRNAs. These findings demonstrate that disruption of translational fidelity in terminally differentiated neurons leads to the accumulation of misfolded proteins and cell death, and provide a novel mechanism underlying neurodegeneration.

Acetylation↗

PubMed2005

A missense mutation in the previously undescribed gene Tmhs underlies deafness in hurry-scurry (hscy) mice.

Mouse deafness mutations provide valuable models of human hearing disorders and entry points into molecular pathways important to the hearing process. A newly discovered mouse mutation named hurry-scurry (hscy) causes deafness and vestibular dysfunction. Scanning electron microscopy of cochleae from 8-day-old mutants revealed disorganized hair bundles, and by 50 days of age, many hair cells are missing. To positionally clone hscy, 1,160 F(2) mice were produced from an intercross of (C57BL/6-hscy x CAST/EiJ) F(1) hybrids, and the mutation was localized to a 182-kb region of chromosome 17. A missense mutation causing a critical cysteine to phenylalanine codon change was discovered in a previously undescribed gene within this candidate interval. The gene is predicted to encode an integral membrane protein with four transmembrane helices. A synthetic peptide designed from the predicted protein was used to produce specific polyclonal antibodies, and strong immunoreactivity was observed on hair bundles of both inner and outer hair cells in cochleae of newborn +/+ controls and +/hscy heterozygotes but was absent in hscy/hscy mutants. Accordingly, the gene was given the name "tetraspan membrane protein of hair cell stereocilia," symbol Tmhs. Two related proteins (>60% amino acid identity) are encoded by genes on mouse chromosomes 5 and 6 and, together with the Tmhs-encoded protein (TMHS), comprise a distinct tetraspan subfamily. Our localization of TMHS to the apical membrane of inner ear hair cells during the period of stereocilia formation suggests a function in hair bundle morphogenesis.

Animals↗

PubMed2002

The harlequin mouse mutation downregulates apoptosis-inducing factor.

Harlequin (Hq) mutant mice have progressive degeneration of terminally differentiated cerebellar and retinal neurons. We have identified the Hq mutation as a proviral insertion in the apoptosis-inducing factor (Aif) gene, causing about an 80% reduction in AIF expression. Mutant cerebellar granule cells are susceptible to exogenous and endogenous peroxide-mediated apoptosis, but can be rescued by AIF expression. Overexpression of AIF in wild-type granule cells further decreases peroxide-mediated cell death, suggesting that AIF serves as a free radical scavenger. In agreement, dying neurons in aged Hq mutant mice show oxidative stress. In addition, neurons damaged by oxidative stress in both the cerebellum and retina of Hq mutant mice re-enter the cell cycle before undergoing apoptosis. Our results provide a genetic model of oxidative stress-mediated neurodegeneration and demonstrate a direct connection between cell cycle re-entry and oxidative stress in the ageing central nervous system.

Aging↗

PubMed2002

Deletion in Catna2, encoding alpha N-catenin, causes cerebellar and hippocampal lamination defects and impaired startle modulation.

Mice homozygous for the cerebellar deficient folia (cdf) mutation are ataxic and have cerebellar hypoplasia and abnormal lobulation of the cerebellum. In the cerebella of cdf/cdf homozygous mice, approximately 40% of Purkinje cells are located ectopically in the white matter and inner granule-cell layer. Many hippocampal pyramidal cells are scattered in the plexiform layers, and those that are correctly positioned are less densely packed than are cells in wild-type mice. We show that fear conditioning and prepulse inhibition of the startle response are also disrupted in cdf/cdf mice. We identify a deletion on chromosome 6 that removes approximately 150 kb in the cdf critical region. The deletion includes part of Catna2, encoding alpha N-catenin, a protein that links the classical cadherins to the neuronal cytoskeleton. Expression of a Catna2 transgene in cdf/cdf mice restored normal cerebellar and hippocampal morphology, prepulse inhibition and fear conditioning. The findings suggest that catenin cadherin cell-adhesion complexes are important in cerebellar and hippocampal lamination and in the control of startle modulation.

Animals↗