Proneurotrophin-3 may induce Sortilin-dependent death in inner ear neurons

• Published in: The European journal of neuroscience Vol. 33; no. 4; pp. 622 - 631
• Main Authors: Tauris, Jacob, Gustafsen, Camilla, Christensen, Erik Ilsø, Jansen, Pernille, Nykjaer, Anders, Nyengaard, Jens R., Teng, Kenneth K., Schwarz, Elisabeth, Ovesen, Therese, Madsen, Peder, Petersen, Claus Munck
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.02.2011
• Subjects: Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; Animals; Apoptosis; Apoptosis - physiology; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Cell surface; Cells, Cultured; Deafness; Degeneration; Ear, Inner - cytology; Embryos; Hearing loss; HEK293 Cells; Humans; Injuries; Inner ear; Mice; Mice, Inbred C57BL; Multiprotein Complexes - metabolism; neonatal inner ear; Neonates; Nerve growth factor; Nervous system; Neural stem cells; Neurons; Neurons - cytology; Neurons - physiology; Neurotrophin 3; Neurotrophin 3 - genetics; Neurotrophin 3 - metabolism; neurotrophins; Ototoxicity; p75NTR; Protein Binding; Protein Precursors - genetics; Protein Precursors - metabolism; Rats; Rats, Wistar; Receptor, Nerve Growth Factor - genetics; Receptor, Nerve Growth Factor - metabolism; spiral ganglion; Spiral Ganglion - cytology; Vps10p domain
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2010.07556.x

The precursor of the neurotrophin (NT) nerve growth factor (NGF) (proNGF) serves physiological functions distinct from its mature counterpart as it induces neuronal apoptosis through activation of a p75 NT receptor (p75NTR) and Sortilin death‐signalling complex. The NTs brain‐derived nerve growth factor (BDNF) and NT3 provide essential trophic support to auditory neurons. Injury to the NT‐secreting cells in the inner ear is followed by irreversible degeneration of spiral ganglion neurons with consequences such as impaired hearing or deafness. Lack of mature NTs may explain the degeneration of spiral ganglion neurons, but another mechanism is possible as unprocessed proNTs released from the injured cells may contribute to the degeneration by induction of apoptosis. Recent studies demonstrate that proBDNF, like proNGF, is a potent inducer of Sortilin:p75NTR‐mediated apoptosis. In addition, a coincident upregulation of proBDNF and p75NTR has been observed in degenerating spiral ganglion neurons, but the Sortilin expression in the inner ear is unresolved. Here we demonstrate that Sortilin and p75NTR are coexpressed in neurons of the neonatal inner ear. Furthermore, we establish that proNT3 exhibits high‐affinity binding to Sortilin and has the capacity to enhance cell surface Sortilin:p75NTR complex formation as well as to mediate apoptosis in neurons coexpressing p75NTR and Sortilin. Based on the examination of wildtype and Sortilin‐deficient mouse embryos, Sortilin does not significantly influence the developmental selection of spiral ganglion neurons. However, our results suggest that proNT3 and proBDNF may play important roles in the response to noise‐induced injuries or ototoxic damage via the Sortilin:p75NTR death‐signalling complex.