bromochloroacetic-acid and Nervous-System-Diseases

Neurotrophic support of developing neurons by neurotrophins is of critical importance in the development of fungiform papillae and taste buds. A number of neurological disorders show a decrease or increase in fungiform papillae or taste sensation. These can be grouped into disorders with reduced papillae (Machado-Joseph disease, Stüve-Wiedemann syndrome, familial dysautonomia, dystonia musculorum, and Behçet's disease) and those with taste defects only (Alzheimer's disease, Huntington's disease, hereditary sensory and autonomic neuropathy type IV, and diabetes mellitus). In addition, Parkinson's disease results in increased taste sensation. Here, we hypothesize that the main problem in these disorders is either not enough or too much neurotrophic support. Proneurotrophic drugs such as some antidepressants and aldose reductase inhibitors may prove useful in the treatment of these sensory and central nervous system disorders. Similarly, antineurotrophic drugs may also be useful in Parkinson's disease. Here we show that the protein involved in familial dysautonomia, IKAP, localizes to keratin filaments in HeLa cells, suggesting a role for the keratin cytoskeleton in neurotrophic support.

Topics: Animals; Carrier Proteins; Heredodegenerative Disorders, Nervous System; Humans; Keratins; Nerve Growth Factors; Nervous System Diseases; Taste Buds; Taste Disorders; Tongue; Transcriptional Elongation Factors

Since the time when I was a postdoctoral fellow under the supervision of Dr. Howard Green, then at the Massachusetts Institute of Technology, I have been interested in understanding the molecular mechanisms underlying growth, differentiation, and development in the mammalian ectoderm. The ectoderm gives rise to epidermal keratinocytes and to neurons, which are the only two cell types of the body that devote most of their protein-synthesizing machinery to developing an elaborate cytoskeletal architecture composed of 10-nm intermediate filaments (IFs). Our interest is in understanding the architecture of the cytoskeleton in keratinocytes and in neurons, and in elucidating how perturbations in this architecture can lead to degenerative diseases of the skin and the nervous system. I will concentrate on the intermediate filament network of the skin and its associated genetic disorders, since this has been a long-standing interest of my laboratory at the University of Chicago.

Topics: Animals; Cytoskeleton; Epidermolysis Bullosa Simplex; Genetic Diseases, Inborn; Humans; Keratins; Mice; Nervous System Diseases; Skin Diseases

By use of immunohistochemistry, we characterized the molecular phenotype of human olfactory epithelial (OE) cells and assessed the nature of the dystrophic olfactory neurites described initially in Alzheimer's disease (AD). Keratin 8 was present in all classes of OE cells. Sustentacular cells lacked other cell type specific polypeptides and were distinguished from neurons and basal cells because the latter two classes of OE cells expressed neural cell adhesion molecules (N-CAMs) and microtubule associated proteins (MAPs), i.e., MAP5. Basal cells expressed nerve growth factor receptors (NGFRs), which distinguished them from olfactory neurons. Unlike their perikarya, olfactory axons expressed vimentin and GAP-43, but not peripherin or neurofilament (NF) proteins. Olfactory nerves were distinguished from other axons because the latter were positive for all three NF subunits and peripherin, in addition to vimentin and GAP-43. Dystrophic neurites in the OE were GAP-43 positive, but they also expressed proteins that were not detected in normal olfactory nerves (i.e., synaptophysin, MAP2, tau, peripherin, NF proteins). Further, rare NF positive olfactory neurons gave rise to NF positive dystrophic neurites. These neurites were present in all 11 AD cases, 11 of 14 subjects with other neurodegenerative diseases, and 6 of 8 neurologically normal adult controls, but no dystrophic neurites were seen in 9 fetal and neonatal cases. We conclude that the molecular phenotype of different human OE cells is distinct and that dystrophic olfactory neurites occur very frequently in neurologically normal adults. The relevance of these neurites to aging or specific disease processes remains speculative.

Topics: Adult; Aged; Aging; Alzheimer Disease; Cell Adhesion Molecules, Neuronal; Epithelial Cells; Epithelium; Female; Humans; Immunohistochemistry; Infant; Infant, Newborn; Infant, Premature; Keratins; Male; Microscopy, Electron; Microtubule-Associated Proteins; Middle Aged; Nerve Growth Factors; Nervous System Diseases; Neurites; Olfactory Mucosa; Receptors, Cell Surface; Receptors, Nerve Growth Factor; Vimentin