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The Journal of Neuroscience, November 1, 2002, 22(21):9378-9386

Identification of the Neuroprotective Molecular Region of Pigment Epithelium-Derived Factor and Its Binding Sites on Motor Neurons

Masako M. Bilak¹, S. Patricia Becerra², Andrea M. Vincent³, Brian H. Moss¹, Maria S. Aymerich², and Ralph W. Kuncl⁴

¹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, ² National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, ³ Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, and ⁴ Department of Biology, Bryn Mawr College, Bryn Mawr, Pennsylvania 19010

Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor (serpin) family, is a survival factor for various types of neurons. We studied the mechanisms by which human PEDF protects motor neurons from degeneration, with the goal of eventually conducting human clinical trials. We first searched for a molecular region of human PEDF essential to motor neuron protection. Using a spinal cord culture model of chronic glutamate toxicity, we show herein that a synthetic 44 mer peptide from an N-terminal region of the human PEDF molecule that lacks the homologous serpin-reactive region contains its full neuroprotective activity. We also investigated the presence and distribution of PEDF receptors in the spinal cord. Using a fluoresceinated PEDF probe, we show that spinal motor neurons contain specific binding sites for PEDF. Kinetics analyses using a radiolabeled PEDF probe demonstrate that purified rat motor neurons contain a single class of saturable and specific binding sites. This study indicates that a small peptide fragment of the human PEDF molecule could be engineered to contain all of its motor neuron protective activity, and that the neuroprotective action is likely to be mediated directly on motor neurons via a single class of PEDF receptors. The data support the pharmacotherapeutic potential of PEDF as a neuroprotectant in human motor neuron degeneration.

Key words: amyotrophic lateral sclerosis; motor neurons; neurodegeneration; neuroprotection; neurotrophic factor; peptide; pigment epithelium-derived factor; serpin; spinal cord

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22219378-09$05.00/0

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