Abstract
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging clinical manifestations, both neurodegenerative diseases share several facets of their complex pathophysiology. Apart from α-synuclein aggregation, an impairment of mitochondrial functions, defective protein clearance systems and excessive inflammatory responses are consistently observed in the brains of PD as well as DLB patients. Leukotrienes are lipid mediators of inflammatory signaling traditionally known for their role in asthma. However, recent research advances highlight a possible contribution of leukotrienes, along with their rate-limiting synthesis enzyme 5-lipoxygenase, in the pathogenesis of central nervous system disorders. This review provides an overview of in vitro as well as in vivo studies, in summary suggesting that dysregulated leukotriene signaling is involved in the pathological processes underlying PD and DLB. In addition, we discuss how the leukotriene signaling pathway could serve as a future drug target for the therapy of PD and DLB.
Highlights
Over the last few years, a considerable amount of evidence was collected underpinning the involvement of dysregulated LT signaling in various pathological processes of neurodegenerative diseases, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB)
The pharmaceutical intervention of the LT synthesis pathway was shown to have beneficial effects on different aspects of the pathogenesis, in vitro as well as in vivo. All these data indicate that the repurposing of the anti-asthmatic drug MTK would be a reasonable approach for the treatment of neurodegenerative diseases
The focus of the in vivo studies performed so far to modulate the LT signaling system in α-synucleinopathies was previously laid on neuroinflammation and neurodegeneration, mainly using toxin-based models for PD
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are two representatives of α-synucleinopathies, a group of age-related neurodegenerative conditions that are characterized by the excessive accumulation of α-synuclein (α-syn), mainly in neurons. PD and DLB, as well as between familial and sporadic forms coding for α-syn, and GBA encoding β-glucocerebrosidase (GCase) is a mutual geof the diseases [6,7,8,9,10] (Figure 1). DLB, α-synuclein accumulations and Lewy bodies are predominantly found in corticalbrain brain areas involved in cognitive impairments. Lewy bodies interfere with a variety of cellularreticulum processes, including mitochondrial and endoplasmic tochondrial and endoplasmic functions, protein degradation systems as well as with th activation of microglia. This review addresses molecular changes associated with the pathogenesis of PD and DLB and discusses the potential role of the leukotriene signaling pathway as an attractive target for the therapy of α-synucleinopathies and related proteinopathies
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