DYSTONIN IS ESSENTIAL FOR MAINTAINING NEURONS CYTOSKELETON ORGANIZATION

The mouse neurological mutant dystonia musculorum (dt) suffers from a hereditary sensory neuropathy. We have previously described the clonin g and characterization of the dt gene, which we named dystonin (Dst). We had shown that dystonin is a neural isoform of bullous pemphigoid a ntigen 1 (Bpag1) with an N-terminal actin-binding domain. It has been shown previously that dystonin is a cytoskeletal linker protein, formi ng a bridge between F-actin and intermediate filaments. Here, we have used two different antibody preparations against dystonin and detected a high-molecular-weight protein in immunoblot analysis of spinal cord extracts. We also show that this high-molecular-weight protein was no t detectable in the nervous system of all dt alleles tested. Immunohis tochemical analysis revealed that dystonin was present in different co mpartments of neurons-cell bodies, dendrites, and axons, regions which are rich in the three elements of the cytoskeleton (F-actin, neurofil aments, and microtubules). Ultrastructural analysis of df dorsal root axons revealed disorganization of the neurofilament network and surpri singly also of the microtubule network. In this context it is of inter est that we observed altered levels of the microtubule-associated prot eins MAP2 and tau in spinal cord neurons of different dt alleles. Fina lly, df dorsal root ganglion neurons formed neurites in culture, but t he cytoskeleton was disorganized within these neurites. Our results de monstrate that dystonin is essential for maintaining neuronal cytoskel eton integrity but is not required for establishing neuronal morpholog y.