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Proneurotrophin‐3 may induce Sortilin‐dependent death in inner ear neurons
Author(s) -
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
Publication year - 2011
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2010.07556.x
Subject(s) - inner ear , neuroscience , biology
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 (p75 NTR ) 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:p75 NTR ‐mediated apoptosis. In addition, a coincident upregulation of proBDNF and p75 NTR has been observed in degenerating spiral ganglion neurons, but the Sortilin expression in the inner ear is unresolved. Here we demonstrate that Sortilin and p75 NTR 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:p75 NTR complex formation as well as to mediate apoptosis in neurons coexpressing p75 NTR 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:p75 NTR death‐signalling complex.