Author:

Abstract:

Neurodegenerative disorders such as Alzheimer's and Parkinson's disease, multiple sclerosis, glaucoma, etc., represent a growing social and economic problem and affect an increasing number of people in our aging society. The world health organisation predicts that by 2040, neurodegenerative diseases will have overthrown cancer in becoming the second most important cause of death after cardiovascular diseases. They drastically diminish life quality and lead to severe impairments, largely because the central nervous system (CNS) of adult mammals has only a limited capacity to replace lost neurons (de novo neurogenesis), or - the focus of this study - to repair damaged axons (axonal regeneration) 1–6. In this project, we propose to use the visual system to investigate the molecules and mechanisms that might contribute to successful axonal regeneration. First, this is of particular relevance for neurodegenerative diseases affecting the retina and optic nerve, such as glaucoma, various optic neuropathies and trauma to the optic nerve. Second, the performed research has a generic character. As the retina and the optic nerve are an integral part of the CNS, the visual system is a powerful model system to gain insights that are applicable to the entire CNS. The dogma ‘The eye is the window to the brain’ can certainly be applied here. Neuroinflammation - particularly the contribution of the innate immune system - has been suggested to be an important mechanism able to trigger the regenerative capacity of the CNS 3,7–15. Whereas the inflammatory response has been considered a harmful process in the past, it is increasingly clear that inflammatory cells actually contribute to CNS repair by their positive impact on - among other things - axonal regeneration 14,16–18. The ever-innovative insights into the dichotomous role of neuroinflammation have now sprouted the idea that directing and instructing the inflammatory machinery may be a better therapeutic objective than suppressing it. Yet, little is known about how inflammation contributes to axonal regeneration in the CNS and the molecules and pathways connecting the two processes remain largely elusive. Over the past decades, intensive research efforts focused on the identification of molecules and pathways involved in axonal regeneration, and the ability to regenerate long nerve fibres in the CNS has evolved from strongly contested to recognized as a potential clinical solution. However, various obstacles must still be overcome before successful regeneration in the CNS will lead to functional recovery 19. The identification of molecules and signal pathways that underlie these processes may lead to important insights that are essential for the development of future innovative successful therapeutic applications. In this project, we set out to use a comprehensive innovative proteomic approach to pinpoint the ligands, receptors and intracellular signalling pathways underlying inflammation-induced axonal regeneration. With this study we aim to take part in the fight for healthy aging. We will focus on the role of the innate immune system during axonal regeneration, and systematically search for factors that link the process of inflammation to successful regeneration.