SARM1 as Potential Gene Target for RGC Degeneration

Article: Scientists pinpoint genetic target with promise for treating many forms of blindness
Source: Trinity College Dublin (Ireland)
Published: February 17, 2022

Sarm1 knockout mice had better optokinetic response/spatial vision
at 2 and 4 months (left graph), consistent for both sexes (right graph)

The heterogeneity of genetic diseases presents a challenge to gene therapy. However, mechanistic commonalities inspire the search for a gene-independent approach. For example, researchers note that mitochondrial dysfunction and axonal degeneration are features of many neurodegenerative diseases, including those that affect the retinal ganglion cells (RGCs) that comprise the optic nerve leading to the brain. Ocular neurodegenerative diseases of the optic nerve manifest in conditions from glaucoma to Leber hereditary optic neuropathy (LHON). In the present study, investigators in Ireland explored the neuroprotective effect of the absence of a prodegenerative NADase called sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1). NAD, or nicotinamide adenine dinucleotide, is a coenzyme central to metabolism in all living cells; enzymatic breakdown of NAD in this case leads to tissue degeneration. The researchers engineered Sarm1  knockout mice and compared them with wild-type controls in a disease model of retinal ganglion cell degeneration through intravitreal injection of rotenone (a natural insecticide and herbicide derived from the roots of Lonchocarpus species). They found that compared to wild-type mice, the Sarm1^−/− mice had better outcomes after rotenone insult, including greater survival of RGCs, preservation of axonal density of optic nerves, increased oxygen consumption rate of primary fibroblasts and other measures of cellular respiration, preservation of photopic negative response (an electrophysiological measure of RGC activity), significantly higher optokinetic response, and overall protection of spatial vision sustained over time to 4 months. The authors conclude, "Collectively, our data indicate that Sarm1  ablation increases mitochondrial bioenergetics and confers histological and functional protection in vivo in the mouse retina against mitochondrial dysfunction, a hallmark of many neurodegenerative conditions including a variety of ocular disorders." 

My rating of this study: ⭐⭐⭐

Finnegan LK, Chadderton N, Kenna PF, et al. "SARM1 Ablation Is Protective and Preserves Spatial Vision in an In Vivo Mouse Model of Retinal Ganglion Cell Degeneration." International Journal of Molecular Sciences.  23(3):1606. 30 January 2022. https://doi.org/10.3390/ijms23031606