Signaling pathways in Parkinson's disease: molecular mechanisms and therapeutic interventions

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, and its treatment remains a big challenge. The pathogenesis of PD may be related to environmental and genetic factors, and exposure to toxins and gene mutations may be the beginning of brain lesions. The identified mechanisms of PD include α-synuclein aggregation, oxidative stress, ferroptosis, mitochondrial dysfunction, neuroinflammation, and gut dysbiosis. The interactions among these molecular mechanisms complicate the pathogenesis of PD and pose great challenges to drug development. At the same time, the diagnosis and detection of PD are also one of obstacles to the treatment of PD due to its long latency and complex mechanism. Most conventional therapeutic interventions for PD possess limited effects and have serious side effects, heightening the need to develop novel treatments for this disease. In this review, we systematically summarized the pathogenesis, especially the molecular mechanisms of PD, the classical research models, clinical diagnostic criteria, and the reported drug therapy strategies, as well as the newly reported drug candidates in clinical trials. We also shed light on the components derived from medicinal plants that are newly identified for their effects in PD treatment, with the expectation to provide the summary and outlook for developing the next generation of drugs and preparations for PD therapy.

Fig. 1

Basic research and drug development history for PD disease and therapy. A2a adenosine receptor type 2a, mGlu metabotropic glutamate receptor, NAM negative allosteric modulator, PAM positive allosteric modulator, EDN embryonic dopamine neuron, PDDPC personalized iPSC-derived dopamine progenitor cell, iPSC induced pluripotent stem cell, DBS deep brain stimulation

Fig. 2

Intracellular α-synuclein homeostasis is maintained via the ubiquitin–proteasome and lysosomal autophagy systems. Impairment of these degradation systems by OS, mitochondrial dysfunction, or neuroinflammation could contribute to α-synuclein accumulation. Furthermore, mutations of genes like LRRK2, DJ-1, Parkin, and Pink1 cause mitochondrial dysfunction and increase cell death. Finally, OS and neuroinflammation appear to be connected

Fig. 3

First, inflammatory cytokines (IL-1β, TNF-α, IL-6) released by activated microglia and astrocytes promote iron accumulation in neurons by upregulating DMT1 and downregulating FPN1. BDNF and GDNF secreted by activated astrocytes reduce iron accumulation in neurons by downregulating DMT1. Second, ROS released from activated microglia promote neuronal OS. Upregulation of Nrf2 and the release of metallothioneins in astrocytes contribute to neuronal resistance to OS. BDNF brain-derived neurotrophic factor, GDNF glial cell line-derived neurotrophic factor, HO-1 heme oxygenase-1, IL-1β interleukin-1β, IL-6 interleukin 6, iNOS inducible nitric oxide synthase, NOX NADPH oxidase, Nrf2 nuclear factor-erythroid factor-2, Tf transferrin, TNF-α tumor necrosis factor α, 12/15-LOX lipoxygenases 12/15, LOOH-PL lipid hydroperoxide–phospholipid, LOH-PL lipid alcohol–phospholipid

Fig. 4

DAMPs (e.g., α-synuclein) trigger an innate immune response upon interaction with pattern recognition receptors in microglial cells. Microglial activation then increases the amount of NF-κB and NLRP3, leading to subsequent cytokine upregulation. Gut dysbiosis sends signals to the CNS and enteric nervous system via metabolites, hormones, and the immune system, thus mediating neuroinflammation

Fig. 5

Natural compounds for PD treatment derived from traditional Chinese medicine