Inherited Retinal degeneration and the therapeutic aspects of Neuron-Glia communication

Retinal Müller glial (RMG) cells

Retinal degenerations remain the most frequent cause of untreatable blindness in the developed world. The molecular causes of such degenerations are manifold and one subgroup of incurable blinding diseases consists of mutation-induced retinal degenerations. Among these, a group of mutations resulting in progressive loss of all photoreceptors in the retina are summarized as disease Retinitis Pigmentosa (RP).

While more than 100 different mutations are known that can independently cause RP, the molecular mechanisms of the degeneration remain largely unknown. However, in order to develop rational therapies a detailed understanding of the exact mechanisms is mandatory. Therefore our lab focuses on the analysis of different animal models for RP.

The variety of pathogenic mutations in the human retina is reflected by a plethora of animal models used to study the disease. We focus on the pathogenic mechanisms in the C3H/Jrd1 mouse that suffers from a fast progressing retinal degeneration and in the B6.CXB1-Pde6brd10/J mouse, that has shown slower degeneration progression. Both animals carry a mutation in the PDE6b gene that affects rod photoreceptors which are responsible for night vision, but as the degeneration progresses also cones and thereby normal daylight vision vanishes.  How this crosstalk works is subject of extensive research also in our group. We further contributed to the understanding of the role of calcium in photoreceptor apoptosis (Hauck et al., MCP 2006) and elaborated the role of a calpain dependant apoptosis pathway in the retina (Paquet-Durand et al., J Neurochem. 2006; Paquet-Durand et al., J Neurosci. 2007).

Despite the molecular variety of degenerative mechanisms, RP finally results in death of all photoreceptor cells. A targeted treatment (gene therapy) for every pathogenic mutation would be desirable but is not feasible. The basis for a prospective successful therapy would be a tissue treatment that a) slows or ends the apoptosis of the mutated cells and b) prevents the spread of the degeneration to other cell classes and c) boost the regeneration of already lost or impaired cellular functions.

Since long it is know that endogenous substances exist that induce the survival, development and function of cells and therefore could provide such a therapy. The first examples of such substances mainly act on neurons and are known as neurotrophins since their discovery by Hamburger and Levi-Montalcini in the 50ies.

In the eye, a natural source of such substances are the retinal Müller glial (RMG) cells. RMG like other glial cells, nourish and protect the retinal neurons and communicate with them in various ways. The RMG also contribute to intrinsic neuroprotection under the influence of disease-induced activation; however, they also transmit as yet unknown paracrine factors upon stimulation with e.g. glial cell line-derived neuroprotective factor (GDNF) (Hauck et al., MCB 2006). With a combined transcriptomics and proteomics approach, we currently dissect the GDNF-induced molecular events in primary RMG and validate the neuroprotective potential of identified candidate factors by in vitro cellular assays (Hauck et al., MCP 2008) and in animal models of Retinitis Pigmentosa (DelRio et al., Glia 2011). We use ex vivo explants of C3H/Jrd1 as in vitro model and now combine it with virus based in vivo expression of the neuroprotective glial factors to elucidate their therapeutic potential.