Therapies to preserve vision in Usher syndrome
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1 USH Talks Therapies to preserve vision in Usher syndrome Monte Westerfield Institute of Neuroscience University of Oregon
2 Usher syndrome is caused by gene mutations Mutations in any one of 11 different genes can cause USH USH genes encode different kinds of proteins USH proteins bind together to form protein complexes USH proteins function in the retina in the eye and in the inner ear USH mutations cause retinal and inner ear cells to die Gene therapies are being developed For gene therapies to work, we need to save cells from dying Treatments that protect cells from dying may enhance the efficacy of gene therapies
3 Usher syndrome is caused by gene mutations Mutations in any one of 11 different genes can cause USH USH genes encode different kinds of proteins USH proteins bind together to form protein complexes USH proteins function in the retina in the eye and in the inner ear USH mutations cause retinal and inner ear cells to die Gene therapies are being developed For gene therapies to work, we need to save cells from dying Treatments that protect cells from dying may enhance the efficacy of gene therapies
4 Usher syndrome is caused by gene mutations Mutations in any one of 11 different genes can cause USH USH genes produce different kinds of proteins USH proteins bind together to form protein complexes USH proteins function in the retina in the eye and in the inner ear USH mutations cause retinal and inner ear cells to die Gene therapies are being developed For gene therapies to work, we need to save cells from dying Treatments that protect cells from dying may enhance the efficacy of gene therapies
5 Usher syndrome is caused by gene mutations Mutations in any one of 11 different genes can cause USH USH genes produce different kinds of proteins USH proteins bind together to form protein complexes USH proteins function in the retina in the eye and in the inner ear USH mutations cause retinal and inner ear cells to die Gene therapies are being developed For gene therapies to work, we need to save cells from dying Treatments that protect cells from dying may enhance the efficacy of gene therapies
6 Usher syndrome is caused by gene mutations Mutations in any one of 11 different genes can cause USH USH genes produce different kinds of proteins USH proteins bind together to form protein complexes USH proteins function in the retina in the eye and in the inner ear USH mutations cause retinal and inner ear cells to die Gene therapies are being developed For gene therapies to work, we need to save cells from dying Treatments that protect cells from dying may enhance the efficacy of gene therapies
7 Usher syndrome is caused by gene mutations Mutations in any one of 11 different genes can cause USH USH genes produce different kinds of proteins USH proteins bind together to form protein complexes USH proteins function in the retina in the eye and in the inner ear USH mutations cause retinal and inner ear cells to die Gene therapies are being developed For gene therapies to work, we need to save cells from dying Treatments that protect cells from dying may enhance the efficacy of gene therapies
8 Usher syndrome is caused by gene mutations Mutations in any one of 11 different genes can cause USH USH genes produce different kinds of proteins USH proteins bind together to form protein complexes USH proteins function in the retina in the eye and in the inner ear USH mutations cause retinal and inner ear cells to die Gene therapies are being developed For gene therapies to work, we need to save cells from dying Treatments that protect cells from dying may enhance the efficacy of gene therapies
9 Usher syndrome is caused by gene mutations Mutations in any one of 11 different genes can cause USH USH genes produce different kinds of proteins USH proteins bind together to form protein complexes USH proteins function in the retina in the eye and in the inner ear USH mutations cause retinal and inner ear cells to die Gene therapies are being developed For gene therapies to work, we need to save cells from dying Treatments that protect cells from dying may enhance the efficacy of gene therapies
10 Usher syndrome is caused by gene mutations Mutations in any one of 11 different genes can cause USH USH genes produce different kinds of proteins USH proteins bind together to form protein complexes USH proteins function in the retina in the eye and in the inner ear USH mutations cause retinal and inner ear cells to die Gene therapies are being developed For gene therapies to work, we need to save cells from dying Therapies that protect cells from dying may enhance the efficacy of gene therapies
11 Mechanosensory cells in the inner ear detect sound Mechanosensory cell in the inner ear
12 Photoreceptor cells in the eye detect light Photoreceptor in the retina (
13 Usher proteins function in mechanosensory cells and photoreceptors Mechanosensory cell Photoreceptor connector region sensory structure synapses
14 Zebrafish provide excellent models for studying Usher syndrome 28 day human human 18 hour zebrafish 18 hour zebrafish Zebrafish: retinal and inner ear cells are similar to humans have the same USH genes USH gene mutations produce retinal and inner ear cell death have advantages for drug screening
15 Measuring vision in young zebrafish
16 Measuring vision in young zebrafish Normal Mutant (Maldonado et al., 2006)
17 Balance defects in USH1B mutants (Teresa Nicolson)
18 Acoustic startle response (Teresa Nicolson)
19 Lack of response in USH1B mutants (Teresa Nicolson)
20 How do USH gene mutations result in cell death? We know that: USH genes produce different kinds of proteins USH proteins bind together to form protein complexes in photoreceptors and mechanosensory cells
21 How do USH gene mutations result in cell death? We know that: USH genes produce different kinds of proteins USH proteins bind together to form protein complexes in photoreceptors and mechanosensory cells So in USH, when and where in the cells is there a problem with these proteins, and how does this lead to cell death?
22 Steps in the production of proteins Mechanosensory cell in the inner ear DNA in nucleus produces RNA
23 Steps in the production of proteins Mechanosensory cell in the inner ear RNA travels to ER DNA in nucleus produces RNA
24 Steps in the production of proteins Mechanosensory cell in the inner ear ER translates RNA to protein RNA travels to ER DNA in nucleus produces RNA
25 Steps in the production of proteins Mechanosensory cell in the inner ear Protein is transported to functional site ER translates RNA to protein RNA travels to ER DNA in nucleus produces RNA
26 Usher protein complexes form at the ER Harmonin
27 Usher mutations block complex formation and Usher proteins accumulate in the ER apoptosis
28 Usher mutations induce ER stress Normal USH1C -/- Normal USH1C -/- (Blanco-Sánchez et al., 2014)
29 Usher mutations lead to ER stress and cell death ER stress apoptosis cell death
30 Exposure to bright light increases the rate of retinal cell death in USH2A mutants Number of dying cells Low light Bright light Normal USH2A -/- Normal USH2A -/- (Jennifer Phillips & Kimberly Lerner )
31 Summary ER stress is proximal cause of cell death in at least some forms of USH
32 Summary ER stress is proximal cause of cell death in at least some forms of USH Approved drugs and drugs in development reduce ER stress in Alzheimer s, Parkinson s, and other neurodegenerative diseases
33 Summary ER stress is proximal cause of cell death in at least some forms of USH Approved drugs and drugs in development reduce ER stress in Alzheimer s, Parkinson s, and other neurodegenerative diseases We use zebrafish models of USH to test these and other potential therapies
34 Summary ER stress is proximal cause of cell death in at least some forms of USH Approved drugs and drugs in development reduce ER stress in Alzheimer s, Parkinson s, and other neurodegenerative diseases We use zebrafish models of USH to test these and other potential therapies Sun glasses are probably important for USH patients to protect the retina (
35 Therapies to preserve vision in Usher syndrome University of Oregon Bernardo Blanco-Sánchez Aurélie Clément Radboud University Medical Center Margo Dona Erwin van Wyjk Taylor Howat Judy Peirce Jennifer Phillips Jeremy Wegner Monte Westerfield Sponsored by the the Usher 1F Collaborative, the National Institute of Child Health & Development, the National Institute on Deafness & Other Communication Disorders, the National Eye Institute, and the Megan and Vision for a Cure Foundations VisionForACure.com
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