Leukotriene Signaling as a Target in α-Synucleinopathies

Biomolecules, 2022 · DOI: https://doi.org/10.3390/biom12030346 · Published: February 23, 2022

Simple Explanation

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are α-synucleinopathies with high unmet medical need. These diseases share complex pathophysiology, including α-synuclein aggregation, mitochondrial dysfunction, defective protein clearance, and excessive inflammatory responses. Leukotrienes are inflammatory signaling lipid mediators traditionally known for their role in asthma. Recent research highlights their possible contribution, along with their synthesis enzyme 5-lipoxygenase, in central nervous system disorders. This review suggests dysregulated leukotriene signaling is involved in pathological processes underlying PD and DLB. It also discusses the leukotriene signaling pathway as a potential drug target for PD and DLB therapy.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
Dysregulated leukotriene signaling is implicated in the pathological processes of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), suggesting a potential therapeutic target.
2
Studies in animal models of PD show that inhibiting leukotriene biosynthesis can attenuate dopaminergic neuronal cell death and reduce neuroinflammation in the nigrostriatal pathway.
3
Montelukast (MTK), a cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, has shown promise in reducing α-synuclein load and improving memory in animal models of dementia with Lewy bodies (DLB).

Research Summary

This review discusses the potential role of leukotriene signaling in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), highlighting the involvement of leukotrienes in neuroinflammation and neurodegeneration. The review emphasizes the therapeutic potential of targeting the leukotriene signaling pathway, particularly through the use of Montelukast, an anti-asthmatic drug, for the treatment of neurodegenerative diseases. The authors call for further research to determine the pathophysiological role of LT signaling in α-synucleinopathies, but existing results suggest that targeting this pathway might be a rational approach for the management of PD and DLB.

Practical Implications

Drug Repurposing

Montelukast, an approved drug for asthma, could be repurposed as a treatment for PD and DLB, potentially offering a new therapeutic approach.

Target Identification

The leukotriene signaling pathway presents a novel target for developing new therapies aimed at reducing neuroinflammation and neurodegeneration in synucleinopathies.

Personalized Medicine

Identifying individuals with specific genetic profiles or inflammatory markers related to leukotriene signaling could enable targeted treatment strategies for PD and DLB.

Study Limitations

1
Limited human data on leukotriene production in PD and DLB.
2
Toxin-based animal models may not fully replicate the gradual progression observed in PD patients.
3
Further research is needed to fully elucidate the role of leukotrienes in autophagic and mitochondrial dysfunction in the context of α-synuclein pathology.

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