This study is focused on study of the function of neurotrophic factors in the brain and their potential for use as therapeutic agents in treatment of human neurodegenerative disease. Among these neurodegenerative diseases are Alzheimers disease, Parkinson's disease, ALS and developmental disorders including Rett syndrome. Rett syndrome (RS) is a neurodegenerative disease affecting only females and is characterized by cognitive deterioration and progressive motor impairment. Neuropathological features of RS include reductions in brain size and weight and hypopigmentation of neurons in the substantia nigra pars compacta (SNpc). We are using terminal deoxynucleotidyl transferase (TDT)-mediated dUTP-biotin nick end labeling (TUNEL), to identify regions of dying cells in brain tissue from RS cases. This technique specifically labels dying cells in situ by end-labeling fragmented nuclear DNA, a process which occurs in many forms of programmed cell death. Through these studies, we have found TUNEL-labeled neuronal nuclei scattered throughout the SNpc in brain tissue from two RS cases (5-6 yr old). No labeled nuclei are detected in control brains. No labeling has been found in other regions of these brains to date. We have also performed immunocytochemistry on serial sections from the same brain areas to visualize tyrosine hydroxylase containing neurons. There are, as expected, dramatically fewer TH positive profiles in the SNpc of Rett brain than in age-matched controls. Although we observed no TUNEL-labeled neurons in the locus coeruleus (LC) of any cases studied, we consistently observed a dramatic reduction of TH positive profiles in Rett LC than control tissue. Interestingly, study of brains from older patients (18-20 yr old) have revealed different results. TUNEL labeling in the SNpc of these cases is found only in what appears to be cellular debris. No similar labelling was found in control brains. We hypothesize that neuronal degeneration in the SNpc of the Rett brains occurs during a limited period early in the disease process. Therefore, brain tissue from older patients (i.e. later in the disease process) will not show the same magnitude of degeneration. Both acidic FGF and GDNF have been identified as trophic factors that can support th DA-ergic neurons of the SNpc. We are initiating studies to determine the usefulness of these factors in treatment of animal models of SN degeneration. Characterizing the mechanisms and time course of neuron death is an important step in identifying potential therapeutic interventions which may be useful in treatment of neurodegenerative disease. During the past year, some of the above data have been accepted for publication and are currently in press: C.A. Kitt and B.J. Wilcox, """""""" Preliminary evidence for neurodegenerative changes in the substantia nigra of Rett syndrome"""""""" NEUROPEDIATRICS.
