Synj 1 modulates functional recovery after motor-incomplete spinal cord injury in male mice carriers of human ApoE4.
Apolipoprotein E epsilon 4 (ApoE4) is the second most common variant of ApoE, being present in ~14% of population. Clinical reports identify ApoE4 as a genetic risk factor for poor outcomes after traumatic SCI and the spinal cord disease (SCD) cervical myelopathy. To date, there are no interventions to mitigate the potent effects of ApoE4 to reduce recovery of function after SCI/D. Studies in human and mouse brain link ApoE4 to elevated levels of synaptojanin 1 (synj1), a lipid phosphatase that dephosphorylates phosphoinositol 4,5-bisphosphate (PIP2) to inositol 4-monophosphate (PIP1). Synj1 regulates rearrangements of the cytoskeleton and the endocytosis and trafficking of synaptic vesicles. We report here that, as compared to ApoE3 mice, levels of synj1 mRNA and protein were elevated in spinal cords from healthy ApoE4 mice associated with lower PIP2 levels. Using a moderate severity model of contusion SCI in mice, we found that genetic reduction of syn1 improved locomotor function recovery at 14 days after SCI in ApoE4 mice without altering spared white matter. Genetic reduction of synj1 did not alter locomotor recover of ApoE3 mice after SCI. Bulk RNA-sequencing revealed that at 14 days after SCI in ApoE4 mice, genetic reduction of synj1 upregulated genes involved in glutaminergic synaptic transmission just above and below the lesion. Overall, our findings provide evidence for a link between synj1 to poor outcomes after SCI in ApoE4 mice through mechanisms that remain speculative but may include greater function of excitatory glutaminergic synapses. Overall design: At 4 months of age, male mice expressing human ApoE3 or ApoE4 variants, that either had one inactive synj1 allele (synj1+/-) or two normal synj1 alleles (synj1+/+), were subjected to a motor-incomplete spinal cord contusion or a laminectomy (sham) at level of thoracic vertebrae T9. At 14 days post-surgery, spinal cord tissues from three animals per group were collected immediately rostral or caudal from the lesion epicenter, and were used for total RNA extraction and later bulk RNA seq studies.