AUTONOMIC NEUROPATHY IN TRANSGENIC MICE CAUSED BY IMMUNOTOXIN TARGETING OF THE PERIPHERAL NERVOUS-SYSTEM

Autonomic neuropathy in several neurodegenerative disorders results fr om disturbance in physiological functions of different cell types in t he central anti peripheral nervous systems, For a clearer understandin g of the etiology and pathogenesis of the autonomic disorders it is ne cessary to create animal models in which degeneration of the causative neuronal types can be induced, Immunotoxin-mediated cell targeting (I MCT) is a novel transgenic mouse technology for eliminating selective cell types with the cytotoxic activity of a recombinant immunotoxin an ti-Tac(Fv)-PE40. In this study we conditionally disrupted peripheral c atecholaminergic cells with IMCT to generate a mouse model developing autonomic failure based on primary defects of the sympathetic nervous system. Transgenic mice expressing human interleukin-2 receptor alpha subunit under the control of the dopamine beta-hydroxylase gene promot er were intravenously treated with a proper dose of anti-Tac(Fv)-PE40. The immunotoxin induced a selective loss of the target cells in perip heral tissues of the transgenic mice and an impairment of catecholamin e metabolism in the tissues, Targeting of the peripheral catecholamine rgic cells resulted in severe and progressive phenotypic abnormalities mainly characterized by cardiac dysfunction, hypoactivity, and hypoth ermia, which explain development of autonomic neuropathy. Our IMCT str ategy is useful for elucidating the involvement of different neuronal types and their interactions in the development and symptom of autonom ic disorders. (C) 1998 Wiley-Liss, Inc.