Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism

Abstract

Regeneration failure after spinal cord injury (SCI) results in part from the lack of a pro-regenerative response in injured neurons, but the response to SCI has not been examined specifically in injured sensory neurons. Using RNA sequencing of dorsal root ganglion, we determined that thoracic SCI elicits a transcriptional response distinct from sciatic nerve injury (SNI). Both SNI and SCI induced upregulation of ATF3 and Jun, yet this response failed to promote growth in sensory neurons after SCI. RNA sequencing of purified sensory neurons one and three days after injury revealed that unlike SNI, the SCI response is not sustained. Both SCI and SNI elicited the expression of ATF3 target genes, with very little overlap between conditions. Pathway analysis of differentially expressed ATF3 target genes revealed that fatty acid biosynthesis and terpenoid backbone synthesis were downregulated after SCI but not SNI. Pharmacologic inhibition of fatty acid synthase, the enzyme generating palmitic acid, decreased axon growth and regeneration in vitro. These results support the notion that decreased expression of lipid metabolism-related genes after SCI, including fatty acid synthase, may restrict axon regenerative capacity after SCI.

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

“…In neurons, axonal PPARγ contributes to the pro-regenerative response after axon injury (Lezana et al, 2016) and our recent study suggest that FASN may generate ligands for PPARγ in neurons (Ewan et al, 2021). We recently demonstrated that in SGC, FASN is required for the activation of PPARα and that PPARα signaling promote axon regeneration in adult peripheral nerves (Avraham et al, 2020).…”

“…Interestingly, dorsal root injury causes up-regulation of the pro-regenerative gene Atf3 (Huang et al, 2006), but only in large diameter neurons, whereas Atf3 and Jun are upregulated in a majority of neurons after 4 peripheral nerve injury (Chandran et al, 2016;Renthal et al, 2020;Seijffers et al, 2007;Tsujino et al, 2000). Spinal cord injury also leads to activation of Atf3 in large diameter neurons, but this is not sufficient to promote regenerative growth (Ewan et al, 2021). Another possibility explaining the slow growth capacity of axons in the injured dorsal root is the contribution of non-neuronal cells.…”

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

“…In neurons, axonal PPARγ contributes to the pro-regenerative response after axon injury ( Lezana et al, 2016 ) and our recent study suggest that FASN may generate ligands for PPARγ in neurons ( Ewan et al, 2021 ). We recently demonstrated that in SGC, FASN is required for the activation of PPARα and that PPARα signaling promote axon regeneration in adult peripheral nerves ( Avraham et al, 2020 ).…”

“…Interestingly, dorsal root injury causes up-regulation of the pro-regenerative gene Atf3 ( Huang et al, 2006 ), but only in large diameter neurons, whereas Atf3 and Jun are upregulated in a majority of neurons after peripheral nerve injury ( Chandran et al, 2016 ; Renthal et al, 2020 ; Seijffers et al, 2007 ; Tsujino et al, 2000 ). Spinal cord injury also leads to activation of Atf3 in large diameter neurons, but this is not sufficient to promote regenerative growth ( Ewan et al, 2021 ). Another possibility explaining the slow growth capacity of axons in the injured dorsal root is the contribution of non-neuronal cells.…”

The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease

“…Axon regeneration failure causes long term structural and functional impairment after a variety of CNS trauma including brain and spinal cord injury (SCI) [ 14 , 15 ]. Previous work has demonstrated that accumulation of certain lipids and dysregulation of lipid metabolism not only contribute to developmental disorders [ 16 , 17 ], axon growth and regeneration failure after CNS trauma [ 6 , 18 ], but also neurodegenerative diseases [ 19 , 20 ]. Lipids are also implicated in myelin formation and serve as bioactive molecules and energy substrates [ 21 , 22 ].…”