Critical role of TPRN rings in the stereocilia for hearing
Year: 2023
Type: article
Abstract: Inner ear hair cells detect sound vibration through the deflection of mechanosensory stereocilia. Cytoplasmic protein TPRN has been shown to localize at the taper region of the stereocilia, and mutations in TPRN cause hereditary hearing loss through an unknown mechanism. Here, using biochemistry and dual stimulated emission depletion microscopy imaging, we show that the TPRN, together with its binding proteins CLIC5 and PTPRQ, forms concentric rings in the taper region of stereocilia. The disruption of TPRN rings, triggered by the competitive inhibition of the interaction of TPRN and CLIC5 or exogenous TPRN overexpression, leads to stereocilia degeneration and severe hearing loss. Most importantly, restoration of the TPRN rings can rescue the damaged auditory function of Tprn knockout mice by exogenously expressing TPRN at an appropriate level in HCs via promoter recombinant adeno-associated virus (AAV). In summary, our results reveal highly structured TPRN rings near the taper region of stereocilia that are crucial for stereocilia function and hearing. Also, TPRN ring restoration in stereocilia by AAV-Tprn effectively repairs damaged hearing, which lays the foundation for the clinical application of AAV-mediated gene therapy in patients with TPRN mutation.
Source: Molecular Therapy
Institutions: Beijing Institute of Technology, Nantong University, Zhongda Hospital Southeast University, State Key Laboratory of Digital Medical Engineering, Southeast University, ShanghaiTech University, University of Electronic Science and Technology of China, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital
Language: English
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,900
Funders: National Natural Science Foundation of China, China Postdoctoral Science Foundation, Fudan University, Department of Science and Technology of Sichuan Province, Southeast University, Jiangsu Postdoctoral Research Foundation, Science, Technology and Innovation Commission of Shenzhen Municipality, ShanghaiTech University, National University's Basic Research Foundation of China, Postdoctoral Research Foundation of China, National Postdoctoral Program for Innovative Talents, National Key Research and Development Program of China, Fundamental Research Funds for the Central Universities
Awards: G1011270330, G1880609003, G2430708696, G2522891566, G267354232, G2976044831, G3426172395, G3632307309, G3852078645, G4069629444, G4210868709, G5037361530, G5417391657, G5591760066, G6004314494, G6171391990, G6737291298, G6911272103, G6983853783, G7284442640, G7640387804, G7693435603, G7814624945, G7844431965, G7891576750, G8030255855, G8162577065, G8388929666, G8454626044, G8999221883, G95219777
OpenAlex ID: W4388599339