Axonal degeneration is a pathology shared by most progressive neurodegenerative diseases, and characterised by the dysfunction and eventual breakdown of interneuronal connections. While the initial causes of axonal pathology vary between disease states, many of the downstream pro-degenerative cascades that the deteriorating axon exhibits are a shared commonality. Sterile alpha and toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is a known critical effector in the pro-degenerative process, with recent literature highlighting its role as a NAD+ hydrolase, and how post-translational modifications may control its structural formation and activity. Neuronal axons separated from their cell body (axotomy) undergo a stereotypical Wallerian degeneration. In the absence of SARM1, degeneration is halted, and stereotypical morphologies are absent. To ascertain the extent of SARM1 involvement in the cellular degenerative process and its possible role in neurodegeneration in a broader sense, a greater understanding of the intracellular proteome before and during degeneration is required.
Here we report in vivo changes to the neuronal and axonal proteome, in retinal and optic nerve samples respectively, using a genetically modified mouse line lacking a functional endogenous SARM1 protein (SARM1-KO) relative to age matched wild type control animals (n = 4 per group) following intraocular administration of the excitotoxin kainic acid (KA). Label-free shotgun proteomics via LC/MS-MS was used in conjuncture with Ti-IMAC phosphopeptide enrichment to identify discrete protein groups and phosphorylated peptides.
Protein groups that increased in expression in response to KA excitotoxicity in the absence of SARM1 include other Toll-like receptors (TIR) involved in pro-inflammatory cytokine recruitment. Decreased phosphorylation at sites on the microtubule-associated protein tau (MAPT), a protein characteristically hyperphosphorylated in Alzheimer’s disease, was observed in the absence of SARM1. Findings in this and ongoing studies into SARM1 provide valuable insights into critical factors involved in the onset of neuronal degeneration.