PATHOGENESIS AND TREATMENT OF NEURODEGENERATIVE DISEASE

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This project seeks to discover improved medical treatments for neurodegenerative disorders affecting motor and cognitive function. Novel approaches to the development of both palliative and protective therapies are currently being explored. In relation to the symptomatic treatment of Parkinsons disease, we have significantly improved our understanding of why the standard therapeutic agent, levodopa, generates increasing complications as the disease advances. Earlier laboratory results indicated that motor dysfunction induced by the chronic nonphysiologic stimulation of dopaminergic receptors expressed on the dendrites of striatal medium spiny neurons is associated with alterations in the sensitivity of nearby glutamatergic receptors, including those of the N-methyl-D-aspartate (NMDA) and the a-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) subtypes. Functional characteristics of these ionotropic channel complexes are regulated by their phosphorylation state. Lesioning the nigrostriatal dopamine system of rats induces parkinsonian signs and increases the tyrosine as well as serine/threonine phosphorylation of striatal NMDA receptor subunits. The intrastriatal administration of certain inhibitors of kinases capable of phosphorylating these subunits produces adopaminomimetic motor response. Treating these parkinsonian rats twice daily with levodopa induces many of the characteristic features of the human motor complication syndrome and further increases the phosphorylation of specific serine/threonine and tyrosine residues on NMDAR2A and NMDAR2B subunits. Again, the intrastriatal administration of selective inhibitors of certain serine and tyrosine kinases reverses the phosphorylation changes and alleviates the motor complications associated with levodopa therapy. Various NMDA receptor antagonists, including some non-competitive channel blockers, act both palliatively and prophylactically in rodent and primate models to reverse the levodopa-induced response alterations. Similarly, our clinical studies have now demonstrated that several NMDA antagonists including amantadine are substantially and enduringly effective in ameliorating motor complications as well as parkinsonian symptoms. Recent observations in animal models further indicated that some AMPA antagonists alleviate while some AMPA agonists exacerbate these levodopa induced complications. Taken together, these results provide increasing support for our view that supersensitivity of certain glutamatergic receptors contributes to the pathogenesis of human levodopa-associated motor complications as well as to the initial appearance of parkinsonian symptoms and that inhibition of these receptors or of their aberrant phosphorylation can substantially reduce motor disability. Controlled proof-of-principle clinical trials to further explore this hypothesis with AMPA and NMDAR2B selective antagonists are now being initiated. Studies addressing the development of neuroprotective treatments for human neurodegenerative disease increasingly suggest that activation of the NF-kB signal transduction cascade may contribute to the apoptotic death striatal GABAergic, nigral dopaminergic, and medial forebrain cholinergic neurons. For example, in rat striatal spiny neurons, excitotoxin induced programmed cell death now appears to involve the following sequence: caspase-3 activation, IkB-alpha degradation, NFKB nuclear translation, followed by increased c-Myc and p53 expression. Blocking the nuclear translocation of NF-kB by any of several means attenuates these excitotoxic responses. In a SY5Y neuronal cell line, degradation of the cytoplasmic protein alpha-synuclein was found to be primarily ubiquitin-proteasome mediated; furthermore, catabolism of the A53T mutant of synuclein, which occurs in a familial form of Parkinsons disease, was markedly impaired, thus favoring the intraneuronal accumulation of this potentially proapoptotic protein. In rat basal forebrain neurons, activation of p75, the low affinity receptor for nerve growth factor, has been observed to selectively enhance the vulnerability of these cholinergic neurons to excitotoxin- as well as amyloid-induced apoptosis via the NFkB signaling pathway. The implications of these convergent findings for the development of protective interventions for human neurodegenerative disease are currently being actively persued.