Glia: initiators and progressors of pathology in Parkinson's disease
Background: Glia are traditionally known as support cells for neurons, and their role in neurodegeneration has been largely considered secondary to neuronal dysfunction. We review newer concepts on glial function and assess glial changes in Parkinson's disease (PD) at the time of disease initiation when α-synuclein is accumulating in brain tissue but there is limited neuronal loss, and also as the disease progresses and neuronal loss is evident. Results: Of the two main types of astrocytes, only protoplasmic astrocytes are involved in PD, where they become nonreactive and accumulate α-synuclein. Experimental evidence has shown that astrocytic α-synuclein deposition initiates the noncell autonomous killing of neurons through microglial signaling. As the disease progresses, more protoplasmic astrocytes are affected by the disease with an increasing microglial response. Although there is still controversy on the role microglia play in neurodegeneration, there is evidence that microglia are activated early in PD and possibly assist with the clearance of extracellular α-synuclein at this time. Microglia transform to phagocytes and target neurons as the disease progresses but appear to become dysfunctional with increasing amounts of ingested debris. Only nonmyelinating oligodendroglial cells are affected in PD, and only late in the disease process. Conclusions: Glial cells are responsible for the progression of PD and play an important role in initiating the early tissue response. In particular, early dysfunction and α-synuclein accumulation in astrocytes causes recruitment of phagocytic microglia that attack selected neurons in restricted brain regions causing the clinical symptoms of PD.