Glutamate-related gene expression changes with age in the mouse auditory midbrain

Tadros, Sherif F.; D’Souza, Mary; Zettel, Martha L.; Liu, Hanjun; Waxmonsky, Nicole C.; Frisina, Robert D.

doi:10.1016/j.brainres.2006.09.081

Cited by 47 publications

(39 citation statements)

References 56 publications

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“…19 PYCR2 deficiency led to increased apoptosis under oxidative stress when cells with homozygous frameshift mutations were treated with H 2 O 2 , and knockdown of PYCR2 ortholog, pycr1b, in a zebrafish model resulted in smaller head/brain, shorter body, down-tilted tail, and hypomotility. 4 …”

Section: Discussionmentioning

confidence: 99%

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PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive

Zaki

Bhat

Sultan³

et al. 2016

Annals of Neurology

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Objective A study was undertaken to characterize the clinical features of the newly described hypomyelinating leukodystrophy type 10 with microcephaly. This is an autosomal recessive disorder mapped to chromosome 1q42.12 due to mutations in PYCR2 gene, encoding an enzyme involved in proline synthesis in mitochondria. Methods From several international clinics, eleven consanguineous families were identified with PYCR2 mutations by whole exome or targeted sequencing, with detailed clinical and radiological phenotyping. Selective mutations from patients were tested for effect on protein function. Results The characteristic clinical presentation of patients with PYCR2 mutations included failure to thrive, microcephaly, craniofacial dysmorphism, progressive psychomotor disability, hyperkinetic movements, and axial hypotonia with variable appendicular spasticity. Patients did not survive beyond the first decade of life. Brain magnetic resonance imaging (MRI) showed global brain atrophy and white matter T2 hyperintensities. Routine serum metabolic profiles were unremarkable. Both nonsense and missense mutations were identified, which impaired protein multimerization. Interpretation PYCR2-related syndrome represents a clinically recognizable condition in which PYCR2 mutations lead to protein dysfunction, not detectable on routine biochemical assessments. Mutations predict a poor outcome, probably as a result of impaired mitochondrial function.

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Section: Discussionmentioning

confidence: 99%

“…P5C can be converted to proline by one of three paralogues in mammals: PYCR1, PYCR2, and PYCRL, linked to the group of rare PYCR-related disorders (Fig 1A). Defects of proline synthesis have major deleterious effects on health, leading to intellectual disability, 2–4 skin and joint hyperelasticity, osteopenia, 5, 6 and cataracts. 7 …”

Section: Introductionmentioning

confidence: 99%

PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive

Zaki

Bhat

Sultan³

et al. 2016

Annals of Neurology

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“…NR1 expression increases in early development, then falls to and/or remains at an intermediate level into adulthood in rat (Akazawa et al 1994) and mouse auditory brainstem (Tadros et al 2007). However, NR1 expression declines in the inferior colliculus (IC) of aging animals, which indicates that NR1 may be involved in the pathogenesis of presbycusis (Osumi et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Age-related hearing loss: GABA, nicotinic acetylcholine and NMDA receptor expression changes in spiral ganglion neurons of the mouse

et al. 2014

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Age-related hearing loss – presbycusis – is the number one communication disorder and most prevalent neurodegenerative condition of our aged population. Although speech understanding in background noise is quite difficult for those with presbycusis, there are currently no biomedical treatments to prevent, delay or reverse this condition. A better understanding of the cochlear mechanisms underlying presbycusis will help lead to future treatments. Objectives of the present study were to investigate gamma-amino butyric acid A (GABAA) receptor subunit α1, nicotinic acetylcholine (nACh) receptor subunit β2, and N-methyl-D-aspartate (NMDA) receptor subunit NR1 mRNA and protein expression changes in spiral ganglion neurons of the CBA/CaJ mouse cochlea, that occur in age-related hearing loss, utilizing quantitative immunohistochemistry and semi-quantitative RT-PCR techniques. We found that auditory brainstem response (ABR) thresholds shifted over 40 dB from 3–48 kHz in old mice compared to young adults. DPOAE thresholds also shifted over 40 dB from 6–49 kHz in old mice, and their amplitudes were significantly decreased or absent in the same frequency range. Spiral ganglion neuron (SGN) density decreased with age in basal, middle and apical turns, and SGN density of the basal turn declined the most. A positive correlation was observed between SGN density and ABR wave 1 amplitude. mRNA and protein expression of GABAAR α1 and AChR β2 decreased with age in SGNs in the old mouse cochlea. mRNA and protein expression of NMDAR NR1 increased with age in SGNs of the old mice. These findings demonstrate that there are functionally-relevant age-related changes of GABAAR, nAChR, NMDAR expression in CBA mouse SGNs reflecting their degeneration, which may be related to functional changes in cochlear synaptic transmission with age, suggesting biological mechanisms for peripheral age-related hearing loss.

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“…For instance, Bao et al [2005] could demonstrate that downregulation of ␤ 2 nicotinic acetylcholine receptors contributes to age-related hearing loss in C57BL/6J mice, while upregulation of the serotonin 2B receptor was detected in the auditory system in aged CBA/CaJ mice with hearing loss [Tadros et al, 2007a]. Also, glutamate-related genes, such as pyrroline-5-carboxylate synthetase and high-affinity glutamate receptor (Slc1a3) are down-and upregulated in the ageing auditory midbrain, respectively [Tadros et al, 2007b]. This illustrates the complexity of age-related hearing loss in mice, and suggests that it may be very complex in human ARHI as well [Keithley et al, 2004].…”

Section: Mouse Modelsmentioning

confidence: 99%

The Complexity of Age-Related Hearing Impairment: Contributing Environmental and Genetic Factors

Eyken¹,

Camp²,

Laer³

2007

Audiol Neurotol

260

205

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Age-related hearing impairment (ARHI) is the most common sensory impairment seen in the elderly. It is a complex disorder, with both environmental as well as genetic factors contributing to the impairment. The involvement of several environmental factors has been partially elucidated. A first step towards the identification of the genetic factors has been made, which will result in the identification of susceptibility genes, and will provide possible targets for the future treatment and/or prevention of ARHI. This paper aims to give a broad overview of the scientific findings related to ARHI, focusing mainly on environmental and genetic data in humans and in animal models. In addition, methods for the identification of contributing genetic factors as well as possible future therapeutic strategies are discussed.

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Glutamate-related gene expression changes with age in the mouse auditory midbrain

Cited by 47 publications

References 56 publications

PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive

PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive

Age-related hearing loss: GABA, nicotinic acetylcholine and NMDA receptor expression changes in spiral ganglion neurons of the mouse

The Complexity of Age-Related Hearing Impairment: Contributing Environmental and Genetic Factors

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