Parkinson's disease: Microglial/macrophage-induced immunoexcitotoxicity as a central mechanism of neurodegeneration

Parkinson's disease is one of the several neurodegenerative disorders that affects aging individuals, with approximately 1% of those over the age of 60 years developing the disorder in their lifetime. The disease has the characteristics of a progressive disorder in most people, with a common pattern of pathological change occurring in the nervous system that extends beyond the classical striatal degeneration of dopaminergic neurons. Earlier studies concluded that the disease was a disorder of alpha-synuclein, with the formation of aggregates of abnormal alpha-synuclein being characteristic. More recent studies have concluded that inflammation plays a central role in the disorder and that the characteristic findings can be accounted for by either mutation or oxidative damage to alpha-synuclein, with resulting immune reactions from surrounding microglia, astrocytes, and macrophages. What has been all but ignored in most of these studies is the role played by excitotoxicity and that the two processes are intimately linked, with inflammation triggered cell signaling enhancing the excitotoxic cascade. Further, there is growing evidence that it is the excitotoxic reactions that actually cause the neurodegeneration. I have coined the name immunoexcitotoxicity to describe this link between inflammation and excitotoxicity. It appears that the two processes are rarely, if ever, separated in neurodegenerative diseases.