Delivered by Dr. Monte Westerfield at the International Symposium on Usher Syndrome.

Download the presentation slides here.

Blanco-Sànchez, B., Clément, A. and Westerfield, M.

Institute of Neuroscience, University of Oregon, Eugene, OR, USA

Abstract:

Human Usher syndrome, the most frequent cause of deaf blindness, is a genetically heterogeneous recessive disease. Patients present with congenital deafness and progressive retinal degeneration. Fourteen loci and eleven genes have been linked to Usher syndrome to date. Surprisingly, these genes encode a wide range of different kinds of proteins including transmembrane adhesion and signaling molecules, intracellular scaffold proteins, and a myosin motor. In vitro binding studies suggest that the scaffold proteins bind the other Usher proteins into a macromolecular complex. Although this model that Usher proteins act together in a complex is an appealing explanation for how the human disease can result from mutation of any one of a number of different genes, it is still controversial. Moreover, the effects of mutations on protein complex formation, subcellular transport, and stability are completely unknown. We have developed an in situ proximity assay to identify if, where, and when Usher proteins form complexes. We find that a subset of Usher proteins preassemble into a complex in the endoplasmic reticulum (ER). In Usher mutants, transport of this complex to the Golgi is disrupted, leading to ER stress and, in some cases, apoptosis. We propose that improper assembly of the Usher complex is a proximal cause of cell death in Usher syndrome. This link between ER stress and apoptosis suggests that therapeutics being developed for the treatment of other neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, will be useful in managing the progression of symptoms in Usher syndrome patients. Although hearing defects are typically congenital due to defects in the mechanoreceptors, hair cells ultimately die, and vision loss is progressive as photoreceptors degenerate over decades. Treatments that delay or reduce cell loss will provide time to patients, while therapies that address the defects are developed and applied to non-degenerating cell populations.
Funding: the National Institute of Child Health & Development, the National Institute of Deafness & Other Disorders, the National Eye Institute, and the Vision for a Cure and Megan Foundations.