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

Retinal neurodegeneration is a hallmark of many vision-threatening diseases, and the receptor sortilin has emerged as a promising therapeutic target due to its involvement in p75NTR-associated neurodegenerative signaling. The effect of sortilin inhibition on acute inner retinal neurodegeneration induced by optic nerve crush was therefore investigated. Pharmacological sortilin inhibition using intravitreal delivery was evaluated in C57BL/6JRj male mice subjected to unilateral crush. Furthermore, the effect of constitutive sortilin deficiency was examined using Sort1-/-mice, and changes in sortilin, p75NTR, and associated injury markers were analyzed. Neither pharmacological inhibition nor 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. Following optic nerve crush, the induction of p75NTR was significantly attenuated in sortilin-deficient retinas. In summary, sortilin inhibition does not preserve inner retinal structure following optic nerve crush, but alters molecular markers associated with glial activation, inflammatory signaling, and neurotrophin-related pathways. Sortilin-dependent pathways may be more relevant in disease contexts characterized by chronic stress and neuroinflammation.