The Role of Glia in Parkinson's Disease
Lee, M.C. van der
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Parkinson’s disease (PD) is a progressive neurodegenerative disorder which is characterized by motor symptoms such as tremor, bradykinesia, rigidity, and postural instability. In addition to the classic motor symptoms, PD patients also suffer from non-motor symptoms such as dementia, anxiety, sleeping disorders, and gastrointestinal problems which seriously impairs their quality of life. An important hallmark of the disorder is the degeneration of dopamine neurons in the substantia nigra (SN) pars compacta and the presence of Lewy bodies (LB) and Lewy neurites (LN) in particular brain areas including the brainstem or cortical regions. Recently, research has shown that simultaneously with the pathological changes glial reactions occur. Controversy remains if these glial reactions occur in response to neurodegeneration in PD or if these glial reactions contribute to neurodegeneration in PD. New insights show that glial reactions might be involved in the initiation and progression of pathology in PD. Glial cells are present in the brain but also in the autonomous system such as in the gastrointestinal system. If glial cells are not merely a response to degeneration in PD and are indeed involved in disease initiation and progression, glial cells in the substantia nigra (SN) and striatum might be involved in the occurrence of motor symptoms while glia in cortical regions might be involved in non-motor symptoms such as dementia and/or anxiety. Glial cells that are present in the gastrointestinal system might be involved in gastrointestinal problems. In this review, research into involvement of glial cells in initiation and progression of PD will be discussed. The presence and location of reactive glia in the brain will be described using animal and human studies. Furthermore, studies on how these reactive glia might contribute to initiation and/or progression of PD will described. Also, it will be discussed which substances are produced by reactive glia and if these might be used as (early) biomarkers for the disease. In addition, it will be studied whether genes that are known to be involved in PD are expressed in glial cells. At last, research into new treatments of PD by inhibiting activation of glial cells will be discussed. It is evident that especially microglia and astrocytes play an important role in PD. It is suggested that these activated phagocytic microglial cells contribute to loss of dopamine neurons in the SN through oxidative stress and production of pro-inflammatory cytokines. Microglial activation occurs before SN dopaminergic neuronal loss occurs which indicates that microglia might be important initiators of PD. However some questions remain to be elucidated. For example the underlying mechanisms how phagocytic microglia selectively target dopaminergic neurons. Astrocytes also appear to play an important role in the initiation of PD. Astrocytes are able to take up alpha-synuclein. Since astrocytes are not able to degrade alpha-synuclein, astrocytes start to produce inflammatory cytokines and ROS. Especially, the ability of astrocytes to recruit microglia makes astrocytes an important link in disease initiation and disease progression. The role of oligodendrocytes remain to be elucidated but evidence suggest that oligodendrocytes are not involved in initiation but might only be involved in progression of the disorder due to demyelination of neurons. Results of studies with anti-inflammatory agents in animal models of PD further support the involvement of glia in the initiation and progression of PD. In addition, to better study the role of inflammation in PD, research should be performed in animal models for PD that are not induced by inflammatory stimuli, for example the alpha-synuclein overexpressing model, since this might bias findings. In the search for effective disease-modifying treatments for PD, a new strategy might be to block inflammation or change the balance towards a more anti-inflammatory state.