USH2020: Using Zebrafish to Develop the First Pharmacotherapy for the Treatment of Hearing Loss Associated with Usher Syndrome Type I due to Variants in MYO7A

July 7, 2020

Alaa Koleilat, PhD

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Presentation Summary:

The mariner (myo7aa-/-) mutant is a zebrafish model for Usher Syndrome Type 1 (USH1). It contains homozygous premature stop codon variants in myo7aa and exhibits deafness, abnormal swimming and balance defects. To further characterize hair cell synaptic elements in myo7aa-/- mutants, we focused on the ribbon synapse and evaluated ultrastructure, number and distribution of immunolabeled ribbons and post-synaptic densities. By transmission electron microscopy, we determined that myo7aa-/- zebrafish have fewer glutamatergic vesicles tethered to ribbon synapses yet maintain a comparable ribbon area. Immunolocalization of CTBP2, the principle protein component of synaptic ribbons, in myo7aa-/- hair cells, showed fewer total ribbon containing cells and an altered distribution of CTBP2 puncta compared to wildtype. We quantified the circular swimming behavior of myo7aa-/- mutant fish and measured a greater turning angle. It was previously shown that L-type voltage-gated calcium channels are necessary for ribbon and post-synaptic density localization, thus we hypothesized and observed that L-type voltage gated calcium channel agonists could change behavioral and synaptic phenotypes in myo7aa-/- mutants in a drug specific manner. Our results indicate that treatment with L-type voltage-gated calcium channel agonists alter hair cell synaptic elements and improve behavioral phenotypes of myo7aa-/- mutants.  Our data supports that L-type voltage-gated calcium channel agonists induce morphological changes at the ribbon synapse—in both the number of tethered vesicles and the distribution of CTBP2 puncta-, shift swimming behavior and improve acoustic startle response.

Speaker Bio:

Alaa Koleilat completed her Bachelors degree in Biology from UCLA in 2013. She then pursued a Masters degree in Biological Sciences from the University of Minnesota, Twin Cities in 2015. She defended her Ph.D. in Biomedical Sciences from Mayo Clinic in March 2020 and is excited to pursue a career in laboratory genetics and genomics starting this summer at Mayo Clinic. Alaa has presented her work at multiple national and international conferences and attended her first Usher Syndrome meeting in Mainz, Germany in 2018 where she presented her thesis work on the zebrafish model of Usher Syndrome Type 1.

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