There are an estimated 12,000 to 20,000 new cases of spinal cord injury (SCI) each year and 1.28 million people in the United States are paralyzed in some form due to SCI. Currently, there are no clinically available treatments that target degraded myelin, one of the primary causes of regenerative failure in the central nervous system (CNS) after acute SCI. Contrary to conventional wisdom, neurons of the central nervous system (CNS) possess substantial regenerative capacity after trauma such as spinal cord injury (SCI). The failure of these neurons to regenerate is therefore not due to intrinsic inability, but rather to inhibitory cues within the CNS microenvironment, including myelin-associated inhibitors (MAIs) and the chondroitin sulfate proteoglycans within the glial scar. While these potent molecular obstacles have been well characterized, the neuronal receptors mediating their ability to blunt neuroregeneration have remained elusive. In this work, I identify LRP1 as a novel receptor of MAG (and likely other MAIs) that mediates inhibition of neurite outgrowth and the inhibitory signaling in neurons. In response to exposure to MAIs, LRP1 forms a signaling complex with p75, which leads to activation of RhoA. Additionally, treatment of myelin with soluble fragments of LRP1, which contain the sequence necessary for MAI binding, also attenuate neuronal growth inhibition. These effects are due to the ability of LRP1 to facilitate MAI-mediated activation of RhoA, which is the necessary and sufficient cellular signal for cessation of axonal extension. Antagonism of LRP1 also attenuates RhoA activation in vivo in rat models of spinal cord injury. LRP1 and p75 also selectively associate from lesion extracts from injured rat spinal cord, and this effect is blocked by infusion of RAP into the lesion site. In total, this work identifies LRP1 as a novel and exciting potential therapeutic target in the regeneration of neurons after damage to the spinal cord

Protein kinase A (PKA) plays critical roles in neuronal function that are mediated by different regulatory (R) subunits. Deficiency in either the RIβ or the RIIβ subunit results in distinct neuronal phenotypes. Although RIβ contributes to synaptic plasticity, it is the least studied isoform. Using isoform-specific antibodies, we generated high-resolution large-scale immunohistochemical mosaic images of mouse brain that provided global views of several brain regions, including the hippocampus and cerebellum. The isoforms concentrate in discrete brain regions, and we were able to zoom-in to show distinct patterns of subcellular localization. RIβ is enriched in dendrites and co-localizes with MAP2, whereas RIIβ is concentrated in axons. Using correlated light and electron microscopy, we confirmed the mitochondrial and nuclear localization of RIβ in cultured neurons. To show the functional significance of nuclear localization, we demonstrated that downregulation of RIβ, but not of RIIβ, decreased CREB phosphorylation. Our study reveals how PKA isoform specificity is defined by precise localization.