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Funded Studies

Comparitive gene expression analysis of the brain in Parkinson's Disease and in familial encephalopathy with neuroserpin inclusion bodies (FENIB): implications for pathogenesis

Parkinson's disease (PD) is a common neurological disorder that affects the control of movement and frequently cognition. Examination of postmortem brain tissue from subjects with Parkinson's disease consistently reveals Lewy bodies (abnormal clumps of protein) in specific types of neurons. Although this cardinal feature of the neuropathology of PD was identified almost a century ago, the relationship of these inclusion bodies in neurons to the onset of the clinical disorder remains unknown. We have recently characterized a new neurodegenerative disorder called familial encephalopathy with neuroserpin inclusion bodies (FENIB) in which mutant forms of a brain protein called neuroserpin misfold and form inclusions (Collins bodies) in many of the same types of neurons affected by Lewy bodies in PD. Some of the clinical findings in FENIB also resemble PD. We have shown that in FENIB there is a direct relationship between the abundance of aggregated protein and the severity of the clinical disorder. This analysis is relatively straightforward since FENIB is a genetic disorder in which every subject inheriting a mutant form of neuroserpin is affected by the disease. FENIB is thus an ideal model system for studying the mechanisms by which protein inclusion bodies cause neuronal dysfunction and death. In contrast, most cases of Parkinson's disease cannot be attributed to any known mutation. We hypothesize that both PD and FENIB result from the inability of certain types of neurons to appropriately or adequately respond to the stress imposed by misfolded proteins. In order to comprehensively assess the cellular responses to protein aggregates, we are using laser microdissection to isolate these cells from post-mortem brain tissue in PD, FENIB, and control subjects, and gene expression microarrays to measure which genes are turned on or off as a consequence.


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