BREAKING Herbs And Phytochemicals News! Taiwanese Study Finds That Pectolinarigenin Can Help With Amyotrophic Lateral Sclerosis (ALS)!

Study Finds that the Phytochemical Pectolinarigenin from the Herb Linaria Vulgaris Improves Oxidative Stress and Apoptosis in Mouse NSC-34 Motor Neuron Cell Lines Induced by C9-ALS-associated Proline-Arginine Dipeptide Repeat Proteins by Enhancing Mitochondrial Fusion Mediated via the SIRT3/OPA1 Axis
 
Herbs And Phytochemicals: Amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, remains a medical challenge due to its progressive degeneration of motor neurons and the absence of effective treatments. In a groundbreaking discovery, researchers at China Medical University in Taichung, Taiwan, have identified a promising avenue for ALS treatment. Their Herbs And Phytochemicals study, centered around the phytochemical Pectolinarigenin (PLG) derived from the traditional medicinal herb Linaria vulgaris, reveals its potential in ameliorating ALS, particularly in cases associated with the C9orf72 mutation (C9-ALS).


                                                               Linaria Vulgaris

Understanding C9-ALS and PR-DPR's Role
C9-ALS, the most prevalent familial ALS form, involves a mutation in the C9orf72 gene, leading to the production of toxic proline-arginine dipeptide repeat proteins (PR-DPR). These proteins wreak havoc within motor neurons, inducing oxidative stress, mitochondrial dysfunction, and apoptosis. The research focused on PR50, a specific form of PR-DPR known for its high toxicity. Previous studies have linked C9-ALS to various mitochondrial damages, including decreased mitochondrial DNA synthesis, altered electron transport chain gene expression, and disruptions in mitochondrial membrane potential.
 
Mitochondrial Dynamics in ALS Pathogenesis
The study delves into the critical role of mitochondrial dynamics in ALS pathogenesis. The balance between mitochondrial fission and fusion is vital for maintaining cellular health, especially in neurons. Optic atrophy 1 (OPA1) and mitofusins (MFN1 and MFN2) drive mitochondrial fusion, while dynamin-related protein 1 (DRP1) and fission 1 (Fis1) regulate fission. ALS-associated PR-DPR disrupts this balance, leading to aberrant mitochondrial dynamics, oxidative stress, and ultimately, cell death.
 
The Neuroprotective Potential of Pectolinarigenin (PLG)
Enter Pectolinarigenin, a natural flavonoid with known antioxidant and anti-inflammatory properties. The researchers established a mouse NSC-34 motor neuron cell line expressing PR50 to mimic C9-ALS conditions. Treatment with PLG demonstrated remarkable neuroprotective effects. It effectively reduced reactive oxygen species (ROS) production and apoptosis induced by PR-DPR.
 
Mechanistic Insights: SIRT3/O PA1 Axis Activation
Further investigations revealed the underlying mechanisms of PLG's neuroprotective effects. PR-DPR hindered mitochondrial fusion proteins, particularly OPA1, and promoted fission proteins. PLG treatment reversed these effects, highlighting its role in restoring mitochondrial dynamics. Notably, PLG increased the expression and deacetylation of OPA1, a process crucial for mitochondrial fusion and resistance to apoptosis. The involvement of the NAD-dependent deacetylase SIRT3 emerged as a key player in this mechanism. PLG's neuroprotective effects were nullified when SIRT3 expression was inhibited, reinforcing the significance of the SIRT3/OPA1 axis in mitigating PR-DPR toxicity.
 
Experimental Results Validate PLG's Therapeutic Potential
The researchers conducted a series of experiments to validate PLG's therapeutic potential. PR50 expression in NSC-34 cells induced apoptosis, disrupted mitochondrial membrane potential, and upregulated apoptotic core proteins. PLG treatment effectively countered these effects, enhancing cell viability and reducing apoptosis. Additionally, PLG restored mitochondrial membrane potential and inhibited ROS production in PR50-expressing cells.
 
PLG's Impact on Mitochondrial Dynamics
The study delved into the impact of PLG on mitochondrial dynamics. PR50 expression increased ROS levels and disrupted mitochondrial activity, effects reversed by PLG treatment. Importantly, PLG restored the expression of mitochondrial fusion proteins (OPA1 and MFN2) and inhibited fission proteins (Fis1 and DRP1), underscoring its role in maintaining mitochondrial homeostasis.
 
PLG-Mediated Inhibition of OPA1 Acetylation
Acetylation of OPA1 emerged as a crucial regulatory mechanism, and PLG demonstrated its inhibitory effect on PR50-induced OPA1 acetylation. SIRT3, a key deacetylase, was downregulated by PR50 expression, but PLG treatment restored SIRT3 levels, further validating its role in regulating OPA1 acetylation.
 
SIRT3 Dependency in PLG-Mediated Neuroprotection
To confirm the centrality of SIRT3 in PLG-mediated neuroprotection, the researchers inhibited SIRT3 expression. This manipulation nullified PLG's ability to promote mitochondrial fusion, inhibit fission, and prevent PR50-induced apoptosis. These findings solidify SIRT3 as a critical upstream regulator in PLG's neuroprotective mechanism.
 
Implications and Future Perspectives
The findings of this Taiwanese study open new horizons in ALS research, particularly in the context of C9-ALS. Pectolinarigenin's ability to modulate mitochondrial dynamics through the SIRT3/OPA1 axis provides a potential avenue for therapeutic development. While this study lays a robust foundation, further preclinical studies are warranted to assess PLG's efficacy in more complex models, such as motor neurons derived from induced pluripotent stem cells of C9-ALS patients or transgenic mice. Additionally, considering the anti-inflammatory properties attributed to PLG in other studies, its potential role in alleviating neuroinflammation in ALS warrants exploration.
 
Conclusion
In conclusion, the discovery of Pectolinarigenin's efficacy in mitigating PR-DPR toxicity marks a significant breakthrough in the pursuit of ALS treatments. This study not only sheds light on the intricate mechanisms underlying ALS pathogenesis but also unveils a potential therapeutic candidate that could pave the way for novel ALS interventions. The comprehensive exploration of mitochondrial dynamics and SIRT3 regulation provides a rich understanding of PLG's neuroprotective mechanisms, making it a promising candidate for further investigation and development.
 
The study findings were published in the peer reviewed journal:Antioxidants.
https://www.mdpi.com/2076-3921/12/11/2008
 
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