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

Authors: Congcong Fang et al. (2023)

Link: https://www.nature.com/articles/s41392-023-01353-3

Background Information:

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide and remains difficult to treat. Its development involves a complex interplay of genetic and environmental factors that trigger harmful processes, including the accumulation of α-synuclein protein clumps, oxidative stress, mitochondrial dysfunction, iron-related cell death (ferroptosis), chronic brain inflammation, and disruption of the gut–brain connection.

Purpose of the Study:

The review aimed to provide a detailed summary of the major molecular pathways that lead to brain cell damage in PD. It also examined how these pathways interact and evaluated current and emerging therapies that target them—including traditional medications, new drugs, gene-based treatments, and natural compounds.

Methods and Data Analysis:

The authors analyzed a wide range of scientific studies—such as cellular and animal experiments, genetic research, and chemical and drug intervention trials. They mapped connections among key biological processes like protein misfolding, oxidative damage, mitochondrial failure, inflammation, ferroptosis, and alterations in the gut microbiome. Their goal was to highlight points where therapeutic intervention could interrupt disease progression.

Key Findings and Conclusions:

The review emphasizes that PD isn't caused by a single issue but rather arises from a network of damaging events that feed into each other—such as α-synuclein clumping increasing oxidative stress, which then harms mitochondria and triggers ferroptosis and inflammation. It also discusses that while current drugs—like levodopa, MAO-B inhibitors, and dopamine agonists—help with symptoms, true disease-modifying therapies are still missing. Promising new targets include antioxidants, iron chelators, anti-inflammatory agents, and drugs that support mitochondria or prevent α-synuclein aggregation. Some of these are already in early-stage clinical trials.

Applications & Limitations:

This comprehensive mapping of PD pathways suggests a shift in treatment strategy: from focusing solely on dopamine replacement to a multi-targeted approach that addresses oxidative damage, mitochondrial health, inflammation, protein aggregation, and gut health. It highlights opportunities for combining existing drugs with newer compounds like iron binders, natural antioxidants, or gene therapies. However, it's important to note that many of these treatments are still being tested, and none have been definitively shown to slow or halt disease progression in large human trials. Challenges remain—including determining the right timing, dosage, and combinations of interventions to effectively manage Parkinson’s disease.