REWIRING THE SPINAL CORD: LIPID REGULATION VIA PERICYTIC IDOL AFTER INJURY

Besides motor and sensory deficits, spinal cord injury (SCI) induces severe metabolic dysregulation, contributing to systemic complications including insulin resistance, dyslipidemia and cardiovascular diseases. Disruption of cholesterol homeostasis appears to be a major driver of this dysfunction, as shown by elevated low-density lipoprotein (LDL) cholesterol in patients. After SCI, pericyte dysfunction contributes to blood-spinal cord barrier (BSCB) breakdown, neuroinflammation and fibrosis, all of which exacerbate metabolic disturbances. However, the role of vascular-associated pericytes in SCI-induced metabolic dysfunction remains poorly understood.
Our lab has identified the Inducible Degrader of the LDL Receptor (IDOL/MYLIP), a key cholesterol metabolism regulator, as a new injury-induced vascular player. Our data demonstrated that IDOL expression is pericyte-specific at 7 days post-injury, with notable enrichment in the caudal region of the lesion. IDOL promotes degradation of the LDL receptor, thereby reducing cholesterol uptake, which may contribute to both vascular dysfunction and systemic metabolic impairment. Nevertheless, the role of IDOL in pericytes and SCI remains unexplored.
We hypothesize that SCI-induced IDOL overexpression in pericytes leads to metabolic dysfunction, positioning pericytes as key metabolic regulators in the neurovascular response to injury. Preliminary data show a dysregulation of the cholesterol homeostasis pathway, notably marked by reduced LDL receptor levels after SCI. In ongoing studies, we are investigating the therapeutic potential of targeting IDOL using antisense oligonucleotide (ASOs) and dissecting the molecular signature of IDOL+ pericytes in the context of injury.