Neuroscience
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Parkinson's Disease (PD) is a chronic and progressive neurodegenerative disorder of unknown etiology. Autopsy findings, genetics, retrospective studies, and molecular imaging all suggest a role for inflammation in the neurodegenerative process. ⋯ We analyze the evidence of immune system involvement in PD susceptibility, specifically in the context of M1 and M2 activation states. Tracking and modulating these activation states may provide new insights into both PD etiology and therapeutic strategies.
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Inflammation has long been associated with the pathogenesis of Parkinson's disease (PD) but the extent to which it is a cause or consequence is sill debated. Over the past decade a number of genes have been implicated in PD. ⋯ Determining how the function of these genes and the proteins they encode are altered in PD has become a priority, as results will likely provide much needed insights into contributing causes. Accumulating evidence indicates that many of these genes function in pathways that regulate aspects of immunity, particularly inflammation, suggesting close associations between PD and immune homeostasis.
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Microglia play major roles in initiation, coordination and execution of innate immunity in the brain. In the adult brain, these include maintenance of homeostasis, neuron and tissue repair, and eliminating infectious agents, apoptotic cells, and misfolded proteins. Some of these activities are accompanied by inflammatory reactions; and others are performed with no inflammatory effects. ⋯ The defects in the intramembrane cleavage result in dysfunction of phagocytosis signaling. The association of TREM2 mutations with neurodegenerative disease also calls for the understanding of the biology and pathological role of non-mutated TREM2 on human brains and microglia. This review provides a summary of current literature in TREM2 and DAP12 from several aspects, and proposes a theory that loss of TREM2 functions might contribute to the immunopathogenic role of microglia in Alzheimer's disease.
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Recent research suggests a complex role for microglia not only in Parkinson's disease but in other disorders involving alpha-synuclein aggregation, such as multiple system atrophy. In these neurodegenerative processes, the activation of microglia is a common pathological finding, which disturbs the homeostasis of the neuronal environment otherwise maintained, among others, by microglia. The term activation comprises any deviation from what otherwise is considered normal microglia status, including cellular abundance, morphology or protein expression. ⋯ Microglia's behavior will therefore be a determinant on the disease's progression. For this reason we believe that the better understanding of microglia's response to alpha-synuclein pathological accumulation across brain areas and disease stages is essential to develop novel therapeutic tools for Parkinson's disease and other alpha-synucleinopathies. In this review we will revise the most recent findings and developments with regard to alpha-synuclein and microglia in Parkinson's disease.