The acid-fast bacterium Nocardia asteroides (NA) is widespread in the environment, and subclinical human infection is common. Experimental infection of mice with this organism results in loss of nigrostriatal dopaminergic neurons, decreased striatal dopamine concentration, and movement abnormalities including head shaking and slowness of movement. These neurochemical and motor alterations are similar to those in Parkinson's disease (PD). The long range goal of our studies is to determine how and why neurons in the substantia nigra pars compacta (SNpc) deteriorate in PD. The objective of this application is to determine the relevance of NA infection as an animal model for PD and a potential causative agent of PD. Our central hypothesis is that CNS NA infection results in the specific loss of dopaminergic neurons and development of motor abnormalities by mechanisms similar to those suggested for PD. This hypothesis has been formulated on the basis of strong preliminary data, suggesting that (a) nocardial toxicity in the SNpc is dopamine neuron-specific, (b) histological findings, including dopamine neuron loss and development of Lewy body-like inclusions, are similar to those in PD, and (c) some of the movement abnormalities in these animals result from striatal dopamine depletion, because they respond to levodopa administration. The rationale for this research is that an understanding of the process by which experimental NA infection causes loss of dopaminergic neurons and motor abnormalities may enhance our ability to prevent this process in PD. Nocardia may be a cause of PD because the organism can survive long-term in the brain as an L-form, suggesting that chronic, subclinical infection could result in neurodegeneration. We are uniquely qualified to perform this research because of our experience with the various in vivo and in vitro aspects of this model. The central hypothesis will be tested and the objective of the application accomplished by pursuing three specific aims: (1) Determine the relationship between neurological and motor abnormalities in mice experimentally infected with NA, and the relevance of this model to PD, (2) Characterize the specificity and mechanism of NA toxicity, and (3) Determine whether evidence for NA infection can be detected in brain specimens from NA-infected mice and from human subjects with PD and Parkinsonian-like syndromes. This work is innovative because it explores the novel hypothesis that an infectious agent may offer a new model for PD and may even contribute to the disease. It is our expectation that these studies will reveal the extent to which this animal model resembles PD, as well as whether persistent NA infection occurs in the PD brain. These outcomes will be significant because they should add to our understanding of the neurodegenerative process in PD, and could lead to improved means of diagnosis and treatment for individuals with this disorder.
