Traumatic Axonal Injury in the Optic Nerve: The Selective Role of SARM1 in the Evolution of Distal Axonopathy

Abstract

Traumatic axonal injury (TAI), thought to be caused by rotational acceleration of the head, is a prevalent neuropathology in traumatic brain injury (TBI). TAI in the optic nerve is a common finding in multiple blunt-force TBI models and hence a great model to study mechanisms and treatments for TAI, especially in view of the compartmentalized anatomy of the visual system. We have previously shown that the somata and the proximal, but not distal, axons of retinal ganglion cells (RGC) respond to DLK/LZK blockade after impact acceleration of the head (IA-TBI). Here, we explored the role of the sterile alpha and TIR-motif containing 1 (SARM1), the key driver of Wallerian degeneration (WD), in the progressive breakdown of distal and proximal segments of the optic nerve following IA-TBI with high-resolution morphological and classical neuropathological approaches. Wild type and Sarm1 knockout (KO) mice received IA-TBI or sham injury and were allowed to survive for 3, 7, 14, and 21 days. Ultrastructural and microscopic analyses revealed that TAI in the optic nerve is characterized by variable involvement of individual axons, ranging from apparent early disconnection of a subpopulation of axons to a range of ongoing axonal and myelin perturbations. Traumatic axonal injury resulted in the degeneration of a population of axons distal and proximal to the injury, along with retrograde death of a subpopulation of RGCs. Quantitative analyses on proximal and distal axons and RGC somata revealed that different neuronal domains exhibit differential vulnerability, with distal axon segments showing more severe degeneration compared with proximal segments and RGC somata. Importantly, we found that Sarm1 KO had a profound effect in the distal optic nerve by suppressing axonal degeneration by up to 50% in the first 2 weeks after IA-TBI, with a continued but lower effect at 3 weeks, while also suppressing microglial activation. Sarm1 KO had no evident effect on the initial traumatic disconnection and did not ameliorate the proximal optic axonopathy or the subsequent attrition of RGCs, indicating that the fate of different axonal segments in the course of TAI may depend on distinct molecular programs within axons.

NAD+, Axonal Maintenance, and Neurological Disease

“…The realization that WD is a molecular program akin to programmed cell death and the related opportunities for understanding pathogenesis and designing novel therapeutics have led to a broader consideration of WD mechanisms beyond the classical axotomy scenario. It now appears that interference with WD protects against axonal degeneration in several disease models associated with axonopathy, including traumatic brain injury (Alexandris et al, 2023 a; Alexandris et al, 2023 b; Bradshaw et al, 2021 ; Henninger et al, 2016 ; Marion et al, 2019 ; Maynard et al, 2020 ; Ziogas and Koliatsos, 2018 ), stroke (Gillingwater et al, 2004 ), EAE (Kaneko et al, 2006 ; Viar et al, 2020 ), neurotoxic parkinsonism (Hasbani and O'Malley, 2006 ; Sajadi et al, 2004 ), diabetic and chemotherapy-induced neuropathy (CIPN) (Geisler et al, 2016 ; Turkiew et al, 2017 ; Wang et al, 2002 ), retinal ischemia and glaucoma (Beirowski et al, 2008 ; Howell et al, 2013 ; Zhu et al, 2013 ), and neuroinflammatory conditions (Ko et al, 2020 ).…”

“…For example, expression of Wld S protects against nigrostriatal axonal degeneration when axons are lesioned with 6-hydroxydopamine in the medial forebrain bundle but not in their terminals (Sajadi et al, 2004 ). Similarly, Sarm1 ablation strongly protects the distal segments of axons after traumatic axonal injury but does not protect proximal axons or cell bodies (Alexandris et al, 2023 a). In addition, the robust axonal protection observed in the first 1 or 2 weeks with inhibition of WD may not always translate in long-term protection, at least to the same degree (Alexandris et al, 2023 a; Viar et al, 2020 ).…”

“…Similarly, Sarm1 ablation strongly protects the distal segments of axons after traumatic axonal injury but does not protect proximal axons or cell bodies (Alexandris et al, 2023 a). In addition, the robust axonal protection observed in the first 1 or 2 weeks with inhibition of WD may not always translate in long-term protection, at least to the same degree (Alexandris et al, 2023 a; Viar et al, 2020 ).…”

ATF2 phosphorylation is essential for neuronal apoptosis, linking the DLK/LZK kinase cascade to JUN upregulation

“…Leucine zipper kinase (LZK or MAP3K13) is a less well studied MAP triple kinase, despite sharing 90% homology of its kinase, catalyJc, and leucine zipper domains with DLK 2 . Although much work has focused on understanding DLK, the importance of LZK in neuron degeneraJon and regeneraJon has only recently been appreciated [3][4][5][6][7] . Moreover, although DLK and LZK have been studied in mouse models, how these two proteins cooperate to regulate neuronal death in human neurons remains unknown.…”