Parkinson Disease Signaling Pathways, Molecular Mechanisms, and Potential Therapeutic Strategies: A Comprehensive Review

Abstract

Parkinson's disease (PD) is considered the second most common neurodegenerative disease worldwide; treating this disease remains quite challenging. Environmental and genetic factors may play a role in the pathophysiology of PD. α-synuclein aggregation, oxidative stress, ferroptosis, mitochondrial failure, neuroinflammation, and gut dysbiosis are among the known risk factors of PD. The pathophysiology of Parkinson's disease is complicated by the interconnections between these molecular pathways, which also present significant obstacles to treatment development. However, due to its complex mechanism and long latency, PD is difficult to diagnose and detect, which presents a barrier to treatment. In addition, the need to develop new treatments for PD is increased by the fact that the majority of traditional therapeutic methods have major side effects and limited effects. Therefore, a deeper understanding of the fundamental mechanisms underlying PD is required. This review provides a comprehensive analysis of the current landscape of PD pathophysiology, paying particular attention to the molecular processes of PD, as well as the traditional research models, clinical diagnostic standards, documented medication therapeutic approaches, and recently disclosed drug candidates in clinical trials. We also highlighted the herbal-derived components that have recently been identified for their effects in the treatment of PD to provide a review and perspectives for the development of the next generation of drugs and preparations for the treatment of PD.

Keywords: Parkinson’s disease (PD); ferroptosis; gut dysbiosis; medicinal plants; mitochondrial dysfunction; neuroinflammation; oxidative stress.

Figure 2

Intracellular α-synuclein balance is preserved through the ubiquitin–proteasome and lysosomal autophagy pathways. Dysfunction of these degradation systems due to oxidative stress, mitochondrial issues, or neuroinflammation may lead to the buildup of α-synuclein. Additionally, gene mutations such as LRRK2, DJ-1, Parkin, and Pink1 lead to mitochondrial impairment and enhance cell mortality. Ultimately, OS and neuroinflammation seem to be linked. This figure was generated by using Microsoft PowerPoint. This figure was modified from Xu Dong-Chen et al., 2023 [103].

Figure 1

Basic research and drug development history for PD disease and therapy, modified from Charvin et al., 2018 [5]. A2a adenosine receptor subtype 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. This figure was generated by using Microsoft PowerPoint.

Figure 3

Initially, inflammatory cytokines (IL-1β, TNF-α, IL-6) secreted by activated microglia and astrocytes enhance iron build-up in neurons by increasing DMT1 expression and decreasing FPN1 expression. Activated astrocytes release BDNF and GDNF, which decrease iron buildup in neurons by lowering DMT1 levels. Secondly, ROS generated by activated microglia enhances neuronal oxidative stress. The increase in Nrf2 and the secretion of metallothioneins in astrocytes enhance neuronal resistance to oxidative stress. BDNF stands for brain-derived neurotrophic factor, GDNF refers to glial cell line-derived neurotrophic factor, HO-1 is heme oxygenase-1, IL-1β denotes interleukin-1β, IL-6 signifies interleukin 6, iNOS indicates inducible nitric oxide synthase, NOX represents NADPH oxidase, Nrf2 is nuclear factor-erythroid factor-2, Tf stands for transferrin, TNF-α is tumor necrosis factor α, 12/15-LOX refers to lipoxygenases 12/15, LOOH-PL means lipid hydroperoxide–phospholipid, and LOH-PL signifies lipid alcohol–phospholipid. This figure was generated by using Microsoft PowerPoint. This figure was modified from Xu Dong-Chen et al., 2023 [103].

Figure 4

DAMPs (such as α-synuclein) initiate an innate immune response when they interact with pattern recognition receptors found in microglial cells. Activation of microglia subsequently raises levels of NF-κB and NLRP3, resulting in the upregulation of cytokines. Gut dysbiosis communicates with the CNS and enteric nervous system through metabolites, hormones, and the immune system, thereby facilitating neuroinflammation. This figure was generated by using Microsoft PowerPoint. This figure was modified from Xu Dong-Chen et al., 2023 [103].