α-synuclein accumulation into dopaminergic neurons is a pathological hallmark of Parkinson’s disease. We previously demonstrated that fatty acid-binding protein 3 (FABP3) is critical for α-synuclein uptake and propagation to accumulate in dopaminergic neurons. FABP3 is abundant in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D_2L). Here, we investigated the importance of dopamine D_2L receptors in the uptake of α-synuclein monomers and their fibrils. We employed mesencephalic neurons derived from dopamine D_2L^−/−, dopamine D2 receptor null (D2 null), FABP3^−/−, and wild type C57BL6 mice, and analyzed the uptake ability of fluorescence-conjugated α-synuclein monomers and fibrils. We found that D_2L receptors are co-localized with FABP3. Immunocytochemistry revealed that TH⁺ D2L^−/− or D2 null neurons do not take up α-synuclein monomers. The deletion of α-synuclein C-terminus completely abolished the uptake to dopamine neurons. Likewise, dynasore, a dynamin inhibitor, and caveolin-1 knockdown also abolished the uptake. D_2L and FABP3 were also critical for α-synuclein fibrils uptake. D_2L and accumulated α-synuclein fibrils were well co-localized. These data indicate that dopamine D_2L with a caveola structure coupled with FABP3 is critical for α-synuclein uptake by dopaminergic neurons, suggesting a novel pathogenic mechanism of synucleinopathies, including Parkinson’s disease.

An increase in the global aging population is leading to an increase in age-related conditions such as dementia and movement disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB). The accurate prediction of risk factors associated with these disorders is crucial for early diagnosis and prevention. Biomarkers play a significant role in diagnosing and monitoring diseases. In neurodegenerative disorders like α-synucleinopathies, specific biomarkers can indicate the presence and progression of disease. We previously demonstrated the pathogenic impact of fatty acid-binding proteins (FABPs) in α-synucleinopathies. Therefore, this study investigated FABPs as potential biomarkers for Lewy body diseases. Plasma FABP levels were measured in patients with AD, PD, DLB, and mild cognitive impairment (MCI) and healthy controls. Plasma FABP3 was increased in all groups, while the levels of FABP5 and FABP7 tended to decrease in the AD group. Additionally, FABP2 levels were elevated in PD. A correlation analysis showed that higher FABP3 levels were associated with decreased cognitive function. The plasma concentrations of Tau, GFAP, NF-L, and UCHL1 correlated with cognitive decline. A scoring method was applied to discriminate between diseases, demonstrating high accuracy in distinguishing MCI vs. CN, AD vs. DLB, PD vs. DLB, and AD vs. PD. The study suggests that FABPs could serve as potential biomarkers for Lewy body diseases and aid in early disease detection and differentiation.

Lewy body diseases (LBD), including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), are neurodegenerative disorders characterized by the intracellular aggregation and accumulation of α-Synuclein (αSyn), leading to neuronal death. Although these diseases primarily present with symptoms affecting the central nervous system (CNS), such as motor and cognitive impairment, increasing research suggests that their roots may be found in the gut. This review summarizes recent findings and key historical insights into the involvement of the gut in αSyn pathology. The topics covered include pathological observations in patients with LBD, animal models investigating the propagation of αSyn from the gut to the brain, intestinal inflammation, alterations in the gut microbiome, and the molecular mechanisms of αSyn pathology within enteric neurons. These topics are essential for understanding the involvement of the gut in αSyn pathology and provide foundational insights that may lead to future therapeutic applications.