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Title: The role of peroxisome defects in hearing impairment
Author: Kochaj, Rafael Matthew
ISNI:       0000 0004 8500 6072
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Peroxisomes are highly dynamic and metabolically active organelles that play an important role in cellular functions, including lipid metabolism and free radical detoxification. Defects in peroxisome biogenesis cause disorders such as Zellweger syndrome, where sensorineural hearing loss is one of the clinical symptoms. Pex3 is a peroxisomal membrane protein essential for the formation of peroxisomes. The aim of this thesis is to establish how peroxisome defects can result in hearing loss, using a mouse with a mutation affecting the Pex3 protein. The Pex3tm1a(EUCOMM)Wtsi mutant mice were generated and screened as part of the Sanger Institute Mouse Genetics Project. Auditory Brainstem Response measurements revealed progressive high frequency hearing impairment in Pex3-deficient mice. Pex3 displayed a strong pattern of expression in all the major structures of the cochlea, including the spiral ganglion neurons, IHCs, OHCs and the stria vascularis. The Pex3 mutation did not affect hair cell morphology or the endocochlear potential at 4 weeks but impaired DPOAEs. Moreover, immunolabelling of the ribbon synapse identified an increased number of mismatched pre-synaptic (Ribeye) and post-synaptic densities (Glur2) in 4-week-old Pex3tm1a mice compared to littermate controls at cochlear regions corresponding to the higher frequencies. The total number of peroxisomes was also reduced in the IHCs at the middle and basal turns of the cochlea. Therefore, inner hair cell synaptic and peroxisome defects are likely to contribute to the high frequency hearing impairment. To determine if Pex3 affects hearing by a direct effect on the inner ear or via systemic influences, genetic manipulation using Cre recombinase was used to inactivate Pex3 only in the inner ear. The resulting Pex3tm1d mutant mice had a severe and progressive hearing impairment affecting all frequencies. The Pex3tm1d mutants showed a reduced number of synapses and peroxisomes in both the IHC and OHC regions. Additionally, the mice exhibited reduced neurofilament expression, indicating axonal damage. Overall, the results suggest that Pex3 is important for normal cochlear innervation. The synaptic, neuronal and peroxisomal defects combined are likely to contribute to the progressive hearing impairment.
Supervisor: Steel, Karen Penelope ; McNaughton, Peter Anthony Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available