Significance of Complement Activation in the Progression of Parkinson's disease

The complement system is composed of a series of proteins which react with each other in an orderly fashion, producing protein fragments (so-called 'complement activation proteins') which can exert significant inflammatory effects. Complement activation serves a protective role by facilitating the removal of microorganisms and tissue debris by the immune system, but excessive activation of this system can result in cellular injury; inappropriate complement activation in the brain, for example, can cause neuronal damage. Studies of complement activation in central nervous system neurodegenerative disorders have focused primarily upon Alzheimer's disease, in which this process is postulated to play an important role. Some evidence suggests that complement activation may also be increased in Parkinson's disease (PD). Because drugs that prevent complement activation are available, if this process is found to play a role in PD, then inhibiting complement activation may slow the progression of the disorder. The objective of this study will therefore be to determine the significance of complement activation in PD. We will test the hypothesis that activation of complement in the PD substantia nigra (the brain region in which major neuronal loss occurs in PD) is correlated with the extent of neuropathology in this region. By using immunoassays and immunocytochemical staining, we will measure the concentrations of complement activation proteins in the aged normal, early-stage PD, and late-stage PD substantia nigra, and will identify the cellular markers in these brain specimens (including intraneuronal inclusion bodies, or Lewy bodies, and oxidative stress) which are associated with complement activation proteins. The information to be obtained in this pilot study should provide important clues as to the importance of complement activation in PD. If our data suggest that this process contributes to PD, then more extensive studies on the relationship between complement activation and PD will be indicated, including consideration of clinical trials with specific complement inhibitors as adjunct therapy in the treatment of PD.