Title: Characterising Novel Regulators of Myelination
Funder: The Academy of Medical Sciences

Abstract: AIM Validate 10 candidates anticipated to have novel pro-myelinating functions in peripheral nervous system (PNS) axons. OBJECTIVES 1: Confirm candidate localisation to axons and/or nodal regions in the PNS 2: Determine which candidates are required for a) myelination and b) Schwann cell recruitment and engagement to PNS axons. 3: Determine the impact of candidate depletion on myelination status (G-ratio). The proper myelination of axons is essential for a fully functioning nervous system. This is achieved via a complex molecular dialogue between axons and glial cells during development and that persists throughout adulthood. In the PNS numerous proteins have been identified as ‘regulators’ of myelination and the pathophysiological source of several neuropathies. One example is ADAM22, a catalytically inactive metalloproteinase localised to the axonal membrane and juxtaparanode. ADAM22, through interaction with its ligand, LGI4, promotes myelination of PNS axons. The first human patients carrying mutations in the ADAM22/LGI4 complex have recently been reported. The patients that survived exhibited a ‘hypomorph’ myelinopathy with numerous clinical manifestations. Like many neuropathies, ADAM22/LGI4 triggered disease has no cure. This is partly result of our limited understanding of the molecular interactions that promote myelination. Characterising more pathways will uncover new therapeutic targets. To this end I have developed an advanced proteomics tool for mapping protein neighbourhoods in mouse PNS axons, and used this to investigate the ADAM22 interactome.

Lay abstract: Our nervous system is a complex network of cables (axons) insulated by a fatty sheath (myelin). Axons are responsible for sending electrical messages around the body. Myelin maximises the speed and efficiency of these electrical messages. To work properly it needs to wrap around axons multiple times, like a tight bandage. Myelin wrapping (myelination) can not be achieved alone, it requires lots of ‘helper proteins’. If any of these helper proteins do not function correctly then myelin isn’t wrapped correctly, leading to diseases called myelinopathies. Seizures, limb deformities and learning difficulties – just some of the conditions suffered by a six year old boy recently reported to have myelination problems. The same report listed two new helper proteins as the probable cause, LGI4 and ADAM22. There is currently no cure for this boy or the others with similar sufferings. This is because there are no drugs to target these particular helper proteins. I recently discovered a group of new helper proteins that we think have important roles during myelination, including the patient described above. The aim of my research is to investigate these helper proteins in more detail using neurons grown in petri dishes. I will remove the newly discovered helper proteins from these neurons and use powerful microscopic tools, that I have personally developed, to see if myelin wrapping is affected. This work will help us find the causes of myelinopathies and find new treatments to help patients suffering from these diseases.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL