Impact of fatty acid-binding proteins and dopamine receptors on α-synucleinopathy

An aging society leads to an increased number of patients with cognitive and movement disorders, such as Parkinson's disease and dementia with Lewy bodies. α-Synuclein accumulation in neuronal cells is a pathological hallmark of α-synucleinopathies. Aberrant soluble oligomeric units of α-synuclein are toxic and disrupt neuronal homeostasis. Fatty acids partially regulate α-synuclein accumulation as well as oligomerization, and fatty acid-binding protein (FABP) associates with the α-synuclein aggregates. Heart-type FABP (hFABP, FABP3) is rich in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D_2L), which is abundant in caveolae. We recently demonstrated that mesencephalic neurons require FABP3 and dopamine D_2L receptors for the caveolae-mediated α-synuclein uptake. Accumulated α-synuclein gets fibrillized and tightly co-localizes with FABP3 and dopamine D_2L receptors, which leads to mitochondrial dysfunction and loss of tyrosine hydroxylase, a rate-limiting enzyme in dopamine production. Furthermore, the inhibition of FABP3 using small-molecule ligands successfully prevents FABP3-induced neurotoxicity. In this review, we focus on the impact of FABP3, dopamine receptors, and other FABP family proteins in the process of α-synuclein propagation and the subsequent aggregate-induced cytotoxicity. We also propose the potential of FABP as a therapeutic target for α-synucleinopathies.