Targeting TLR4 in Parkinson's disease: mechanisms and therapeutic prospects

Parkinson's disease (PD) is the second most common neurodegenerative disorder, which is on the rise and poses an increasing burden on health care systems across the world. The essential factors of dopaminergic neurodegeneration in PD are neuroinflammation, α-synuclein (α-syn) aggregation, mitochondrial dysfunction, and gut microbiota dysbiosis. The toll-like receptor 4 (TLR4), one of the central elements of the innate immune system, has become one of the key controls of PD pathogenesis. Studies have shown that TLR4 is overexpressed in PD and mediates neuroinflammatory reactions through the activation of downstream signaling pathways, i.e., MyD88-dependent and TRIF-dependent pathways. TLR4 can also mediate context-dependent effects, such as its prolonged stimulation can worsen neuroinflammation and neuronal damage, whereas in the initial stages of the disease, it can be engaged in the process of clearing pathological α-syn aggregates. This review presents the recent evidence of clinical research, animal models, and in vitro research on the role of TLR4 in PD. The review also discusses the molecular pathways of neuron inflammation caused by TLR4 and its communication with α-syn aggregation, mitochondrial impairment, and the gut-brain axis. It also covers some of the newer therapeutic approaches that have been developed to address TLR4 signaling, such as natural compounds, drug repurposing strategies, and microbiota-based therapies. Taking into account these effects, TLR4 is regarded as a potential therapeutic target of PD. The comprehensive insight into its dual regulation capabilities can be employed to formulate more effective disease-modifying treatments.