Microglial polarisation imbalance and receptor-targeted therapeutics in Parkinson's disease

Parkinson's Disease (PD) is a progressive neurodegenerative disease, which is mainly characterised by the selective depletion of dopaminergic neurons in the substantia nigra and deposition of misfolded aggregates of α-synuclein. It is increasingly being observed that neuroinflammation, mitochondrial dysfunction, and lost neurotrophic support are interacting factors that drive disease progression. The aggregated 1-synuclein triggers an anti-inflammatory phenotype and pro-inflammatory phenotypes in activated microglia, which produce cytokines and reactive oxygen species, aggravating stress in neurons. At the same time, mitochondrial dynamic dysfunction increases oxidative injury, which makes neurons sensitive to degeneration. The low concentration of neurotrophic factors, especially the brain-derived neurotrophic factor (BDNF), impairs the innate ability of the brain to repair itself and maintain its synapses. These pathological processes gradually create a loop of self-feeding, which results in prolonged inflammation, loss of proteostasis, and gradual loss of dopaminergic neurons. This network is interconnected, and understanding it is crucial in the creation of therapies that attempt to restore proteostasis, inhibit inflammation, and increase neurotrophic signalling to delay or prevent PD progression.