Abstract
Progressive hearing loss is very common in the human population but we know little about the underlying molecular mechanisms. Synaptojanin2 (Synj2) has been reported to be involved, as a mouse mutation led to a progressive increase in auditory thresholds with age. Synaptojanin2 is a phosphatidylinositol (PI) phosphatase that removes the five-position phosphates from phosphoinositides, such as PIP2 and PIP3, and is a key enzyme in clathrin-mediated endocytosis. To investigate the mechanisms underlying progressive hearing loss, we have studied a different mutation of mouse Synj2 to look for any evidence of involvement of vesicle trafficking particularly affecting the synapses of sensory hair cells. Auditory brainstem responses (ABR) developed normally at first but started to decline between 3 and 4 weeks of age in Synj2tm1b mutants. At 6 weeks old, some evidence of outer hair cell (OHC) stereocilia fusion and degeneration was observed, but this was only seen in the extreme basal turn so cannot explain the raised ABR thresholds that correspond to more apical regions of the cochlear duct. We found no evidence of any defect in inner hair cell (IHC) exocytosis or endocytosis using single hair cell recordings, nor any sign of hair cell synaptic abnormalities. Endocochlear potentials (EP) were normal. The mechanism underlying progressive hearing loss in these mutants remains elusive, but our findings of raised distortion product otoacoustic emission (DPOAE) thresholds and signs of OHC degeneration both suggest an OHC origin for the hearing loss. Synaptojanin2 is not required for normal development of hearing but it is important for its maintenance.
Highlights
We report our investigations into the mechanisms underlying one form of progressive hearing loss found in mice with a synaptojanin2 (Synj2) mutation
The progressive hearing loss was associated with stereocilia fusion of outer hair cells (OHC) and hair cell degeneration from as early as 2 weeks old starting in the basal turn of the cochlea, progressing with age to include inner hair cells (IHCs) and extending towards the middleapical part of the cochlea
To investigate the mechanisms underlying progressive hearing loss, we have studied a different mutation of Synj2 to look for any evidence of involvement of vesicle trafficking affecting the synapses of sensory hair cells
Summary
Hearing impairment is the most common sensory loss in people at any age and in the UK more than 70% of people over 70 years old and 40% of over 50 years old have age-related hearing loss (ARHL, or presbyacusis). We report our investigations into the mechanisms underlying one form of progressive hearing loss found in mice with a synaptojanin (Synj2) mutation. Zebrafish with a Synj mutation show basal blebs in sensory hair cells, a sign of imbalance between exo- and endocytosis, together with an increase in large coated vesicles and a reduction in numbers of tethered vesicles and reserve pool vesicles (Trapani et al, 2009). The progressive hearing loss was associated with stereocilia fusion of outer hair cells (OHC) and hair cell degeneration from as early as 2 weeks old starting in the basal turn of the cochlea, progressing with age to include inner hair cells (IHCs) and extending towards the middleapical part of the cochlea. To investigate the mechanisms underlying progressive hearing loss, we have studied a different mutation of Synj to look for any evidence of involvement of vesicle trafficking affecting the synapses of sensory hair cells. The mechanism underlying progressive hearing loss in these mutants remains elusive, but our findings of raised distortion product otoacoustic emission (DPOAE) thresholds and signs of OHC degeneration both suggest an OHC origin for the hearing loss
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