02104nas a2200265   4500000000100000000000100001008004100002260001500043100002700058700002000085700002200105700002100127700003000148700002100178700002100199700002000220700002400240700001800264700001800282700001600300700002200316245011600338856006400454520132000518       2024                            d  c2024-06-161 aDiana Tavares Ferreira1 aBreanna Q. Shen1 aJuliet M. Mwirigi1 aStephanie Shiers1 aIshwarya Sankaranarayanan1 aMiriam Kotamarti1 aNikhil N. Inturi1 aKhadijah Mazhar1 aEroboghene E. Ubogu1 aGeneva Thomas1 aTrapper Lalli1 aDane Wukich1 aTheodore J. Price00aDeciphering the molecular landscape of human peripheral nerves: implications for diabetic peripheral neuropathy  uhttps://www.biorxiv.org/content/10.1101/2024.06.15.599167v13 aDiabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus that is caused by metabolic toxicity to peripheral axons. We aimed to gain deep mechanistic insight into the disease process using bulk and spatial RNA sequencing on tibial and sural nerves recovered from lower leg amputations in a mostly diabetic population. First, our approach comparing mixed sensory and motor tibial and purely sensory sural nerves shows key pathway differences in affected nerves, with distinct immunological features observed in sural nerves. Second, spatial transcriptomics analysis of sural nerves reveals substantial shifts in endothelial and immune cell types associated with severe axonal loss. We also find clear evidence of neuronal gene transcript changes, like PRPH, in nerves with axonal loss suggesting perturbed RNA transport into distal sensory axons. This motivated further investigation into neuronal mRNA localization in peripheral nerve axons generating clear evidence of robust localization of mRNAs such as SCN9A and TRPV1 in human sensory axons. Our work gives new insight into the altered cellular and transcriptomic profiles in human nerves in DPN and highlights the importance of sensory axon mRNA transport as an unappreciated potential contributor to peripheral nerve degeneration.