SARM1 deficiency promotes rod and cone photoreceptor cell survival in a model of retinal degeneration

Abstract

Retinal degeneration is the leading cause of incurable blindness worldwide and is characterised by progressive loss of light-sensing photoreceptors in the neural retina. SARM1 is known for its role in axonal degeneration, but a role for SARM1 in photoreceptor cell degeneration has not been reported. SARM1 is known to mediate neuronal cell degeneration through depletion of essential metabolite NAD and induction of energy crisis. Here, we demonstrate that SARM1 is expressed in photoreceptors, and using retinal tissue explant, we confirm that activation of SARM1 causes destruction of NAD pools in the photoreceptor layer. Through generation of rho−/−sarm1−/− double knockout mice, we demonstrate that genetic deletion of SARM1 promotes both rod and cone photoreceptor cell survival in the rhodopsin knockout (rho−/−) mouse model of photoreceptor degeneration. Finally, we demonstrate that SARM1 deficiency preserves cone visual function in the surviving photoreceptors when assayed by electroretinography. Overall, our data indicate that endogenous SARM1 has the capacity to consume NAD in photoreceptor cells and identifies a previously unappreciated role for SARM1-dependent cell death in photoreceptor cell degeneration.

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

“…As NAD + loss is a common pathology of many retinal diseases, this raises the possibility that SARM1 activation may contribute to a wide range of retinal disorders. In support of this conjecture, recent studies found that SARM1 promotes retinal degeneration in X-linked retinoschisis 62 and rhodopsin-deficient mice 63 .…”

SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

“…As NAD + loss is a common pathology of many retinal diseases, this raises the possibility that SARM1 activation may contribute to a wide range of retinal disorders. In support of this conjecture, recent studies found that SARM1 promotes retinal degeneration in X-linked retinoschisis ( Molday et al, 2007 ) and rhodopsin-deficient mice ( Ozaki et al, 2020 ).…”

Structural basis for SARM1 inhibition and activation under energetic stress

“…Subsequently, studies have demonstrated that SARM1 is also a key part of a highly conserved axonal death pathway that is activated by nerve injury ( Gerdts et al, 2013 ; Osterloh et al, 2012 ). Notably, SARM1 deficiency confers protection against axonal degeneration in several models of neurodegenerative conditions ( Kim et al, 2007 ; Ko et al, 2020 ; Ozaki et al, 2020 ; Uccellini et al, 2020 ), making SARM1 a compelling drug target to protect axons in a variety of axonopathies ( Krauss et al, 2020 ; Loring et al, 2020 ).…”