Applicant:
Melitta Schachner, Zentrum für Molekulare Neurobiologie Universitaet Hamburg Falkenried 94 20251 Hamburg
E-Mail: melitta.schachner@zmnh.uni-hamburg.de

Neural cell adhesion molecules have been shown to be good neurite outgrowth promoters. Among them, L1 promotes neurite elongation on Schwann cells by a homophilic binding mechanism between Schwann cells and neurons. L1 is upregulated by neurons and Schwann cells after a peripheral nerve lesion and has been implicated in axon regeneration. A critical role of L1 is also indicated by the recent finding that different mutations in the protein result in severe human neuropathological disorders. Up to the present time, almost 100 different mutations in the L1 gene have been shown to cause three related syndromes: hydrocephalus as a result of stenosis of the Aqueduct of Sylvius (HSAS); mental retardation, aphasia, shuffling gait, and adducted thumbs (MASA); and X-linked (or complicated) spastic paraplegia (SP-1).

To convey neurite outgrowth conductive properties to L1 expressing neurons, we propose to generate peptides that bind to L1 and enhance neurite outgrowth not only in vitro, but also in vivo, hopefully overcoming the largely inhibitory environment for neurite outgrowth in vivo. Furthermore, metabolically stable peptides will be generated that will then be used in a mammalian model of spinal cord regeneration.

Neural cell adhesion molecules have been shown to be good neurite outgrowth promoters and promoters of neuronal survival in vitro. Among them, the immunoglobulin superfamily adhesion molecule L1 promotes neurite outgrowth on the glial cells of the peripheral nervous system, the Schwann cells, by a homophilic, that is self-binding mechanism between Schwann cells and neurons. L1 is upregulated in a neurotrophin mediated manner by neurons and Schwann cells after a peripheral nerve lesion and thus has been implicated in axon regeneration, not only in the peripheral, but also central nervous system. To convey neurite outgrowth conducive properties to L1 expressing neurons, we have generated a library of peptides that bind to L1 and, as selected by phage display approaches, that enhance neurite outgrowth and neuronal survival not only in vitro, but as recently found also in vivo. Thus, these peptides can overcome the inhibitory environment for outgrowth in the adult central nervous system. We have started to produce not only more metabolically stable peptides, but also peptides more stabilised in their configuration that have been used in vitro to assay for their ability to enhance neurite outgrowth and neuronal survival.These are presently being used in a compression model for spinal cord regeneration that we have established in mice. It is hoped that these studies will contribute to our understanding of the molecular mechanisms that underlie neuroprotective influences of exogenously applied compounds in the adult central nervous system.