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bioRxiv · 10.64898/2026.05.08.723723

Sortilin deficiency alters baseline retinal homeostasis and injury-induced signaling without affecting optic nerve crush-induced neurodegeneration

Jakobsen, T. S.·Lindholm, A. B.·Bek, T.·Nykjaer, A.·Corydon, T. J.·Askou, A. L.
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Abstract

The effect of sortilin inhibition on acute inner retinal neurodegeneration induced by optic nerve crush was investigated. Pharmacological sortilin inhibition using intravitreal delivery of a polyclonal antibody or a small-molecule inhibitor was evaluated in C57BL/6JRj male mice subjected to unilateral crush. Inner retinal thickness was evaluated by optical coherence tomography, and retinal ganglion cell density was determined in retinal flat mounts. Furthermore, the effect of constitutive sortilin deficiency was examined using Sort1-/- mice. Changes in protein and mRNA levels of sortilin, p75NTR, and associated injury markers were analyzed. Neither pharmacological inhibition or constitutive loss of sortilin protected against inner retinal thinning or retinal ganglion cell loss following optic nerve crush. A transient 1.4-fold increase in p75NTR mRNA was observed early after injury, accompanied by a two-fold increase in protein levels. While sortilin expression remained largely unchanged, sortilin deficiency was associated with an altered baseline retinal state, including increased GFAP, p75NTR, and proBDNF levels. Following optic nerve crush, the induction of p75NTR was significantly attenuated in sortilin-deficient retinas compared with wild type, without affecting the extent of RGC degeneration. In summary, sortilin inhibition does not preserve inner retinal structure following optic nerve crush, but modulates glial activation, inflammatory signaling, and proneurotrophin dynamics. These findings indicate that sortilin-dependent pathways are not key drivers of optic nerve crush-induced neurodegeneration but may be more relevant in disease contexts characterized by chronic stress and neuroinflammation.

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Jakobsen, T. S., Lindholm, A. B., Bek, T., Nykjaer, A., Corydon, T. J., Askou, A. L.. 2026-05-12. Sortilin deficiency alters baseline retinal homeostasis and injury-induced signaling without affecting optic nerve crush-induced neurodegeneration. https://doi.org/10.64898/2026.05.08.723723

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