The dual nature of the nerve growth inhibitor Nogo-A

Traumatic injury to the adult spinal cord typically results in irreparable motor and sensory deficits. Myelin of the adult central nervous system (CNS) has been attributed to impede regenerating nerve fibers. Nogo-A is possibly the best characterized of a variety of neurite growth inhibitors present in CNS myelin sheaths. It exerts its inhibitory effect via two distinct protein domains, the C-terminal Nogo-66 and the central inhibitory domain NiG. While a neuronal receptor complex for Nogo-66 has been characterized in the past few years, NiG is still an orphan ligand. By using NiG as a bait, we intend to pull-down candidates for a neuronal receptor from extracts of brain plasma membranes in a novel proteomics based experimental approach. Interestingly, Nogo-A is also found in the endoplasmic reticulum (ER) of both neurons and glial cells. As we have shown recently, ER-associated Nogo-A promotes growth and arborization of dendrites in CNS neurons, indicating a dual functionality based on differential subcellular localization. To elucidate the underlying mechanisms, we propose to screen for ER-specific interactors of Nogo-A in microsomal extracts of brain tissue. By identifying specific binding partners of Nogo-A in distinct subcellular compartments, we believe to profoundly advance knowledge on the diverse functionality of this clinically relevant protein.

Traumatic injury to the central nervous system (CNS) typically results in irreparable deficits. Myelin of the adult CNS has been attributed to impede regenerating nerve fibers. Nogo-A is possibly the best characterized of a variety of neurite growth inhibitors present in CNS myelin sheaths. Interestingly, Nogo-A is found not only in myelin producing glia cells, but also in neurons themselves. As we have shown recently, neuronal Nogo-A promotes growth and arborization of processes of CNS neurons, indicating a dual functionality based on differential subcellular localization. To elucidate the underlying mechanisms, we intended to screen for neuronal interactors of Nogo-A. We have successfully completed this project by identifying and characterizing a novel interactor of Nogo-A, Apg-1. Apg-1 is a neuronal stress protein which is up-regulated under a number of stress scenarios in the brain, including ischaemia. We will continue on this new finding and investigate the role of Nogo-A in neuronal stress management, with a particular focus on ischaemia, which typically results from a stroke in the brain.