FABP2 is Involved in Intestinal α-Synuclein Pathologies.

BACKGROUND: Recently, the hypothesis that pathological α-Synuclein propagates from the gut to the brain has gained attention. Although results from animal studies support this hypothesis, the specific mechanism remains unclear. This study focused on the intestinal fatty acid-binding protein (FABP2), which is one of the subtypes of fatty acid binding proteins localizing in the gut, with the hypothesis that FABP2 is involved in the gut-to-brain propagation of α-synuclein. The aim of this study was to clarify the pathological significance of FABP2 in the pathogenesis and progression of synucleinopathy. METHODS: We examined the relationship between FABP2 and α-Synuclein in the uptake of α-Synuclein into enteric neurons using primary cultured neurons derived from mouse small intestinal myenteric plexus. We also quantified disease-related protein concentrations in the plasma of patients with synucleinopathy and related diseases, and analyzed the relationship between plasma FABP2 level and progression of the disease. RESULTS: Experiments on α-Synuclein uptake in primary cultured enteric neurons showed that following uptake, α-Synuclein was concentrated in areas where FABP2 was localized. Moreover, analysis of the plasma protein levels of patients with Parkinson's disease revealed that the plasma FABP2 and α-Synuclein levels fluctuate with disease duration. The FABP2/α-Synuclein ratio fluctuated more markedly than either FABP2 or α-Synuclein alone, depending on the duration of disease, indicating a higher discriminant ability of early Parkinson's disease patients from healthy patients. CONCLUSIONS: These results suggest that FABP2 potentially contributes to the pathogenesis and progression of α-synucleinopathies. Thus, FABP2 is an important molecule that has the potential to elucidate the consistent mechanisms that lead from the prodromal phase to the onset and subsequent progression of synucleinopathies.

Using Fatty Acid-Binding Proteins as Potential Biomarkers to Discriminate between Parkinson's Disease and Dementia with Lewy Bodies: Exploration of a Novel Technique.

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.

Epsin2, a novel target for multiple system atrophy therapy via α-synuclein/FABP7 propagation.

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the accumulation of misfolded α-synuclein (αSyn) and myelin disruption. However, the mechanism underlying αSyn accumulation in MSA brains remains unclear. Here, we aimed to identify epsin-2 as a potential regulator of αSyn propagation in MSA brains. In the MSA mouse model, PLP-hαSyn mice, and FABP7/αSyn hetero-aggregate-injected mice, we initially discovered that fatty acid-binding protein 7 (FABP7) is related to MSA development and forms hetero-aggregates with αSyn, which exhibit stronger toxicity than αSyn aggregates. Moreover, the injected FABP7/αSyn hetero-aggregates in mice selectively accumulated only in oligodendrocytes and Purkinje neurons, causing cerebellar dysfunction. Furthermore, bioinformatic analyses of whole blood from MSA patients and FABP7 knockdown mice revealed that epsin-2, a protein expressed in both oligodendrocytes and Purkinje cells, could potentially regulate FABP7/αSyn hetero-aggregate propagation via clathrin-dependent endocytosis. Lastly, adeno-associated virus type 5-dependent epsin-2 knockdown mice exhibited decreased levels of αSyn aggregate accumulation in Purkinje neurons and oligodendrocytes, as well as improved myelin levels and Purkinje neuron function in the cerebellum and motor performance. These findings suggest that epsin-2 plays a significant role in αSyn accumulation in MSA, and we propose epsin-2 as a novel therapeutic target for MSA.

Dopamine D2 Long Receptors Are Critical for Caveolae-Mediated α-Synuclein Uptake in Cultured Dopaminergic Neurons.

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 (D2L). Here, we investigated the importance of dopamine D2L receptors in the uptake of α-synuclein monomers and their fibrils. We employed mesencephalic neurons derived from dopamine D2L -/-, 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 D2L 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. D2L and FABP3 were also critical for α-synuclein fibrils uptake. D2L and accumulated α-synuclein fibrils were well co-localized. These data indicate that dopamine D2L 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.