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. alpha-Synuclein accumulation in neuronal cells is a pathological hallmark of alpha-synucleinopathies. Aberrant soluble oligomeric units of alpha-synuclein are toxic and disrupt neuronal homeostasis. Fatty acids partially regulate alpha-synuclein accumulation as well as oligomerization, and fatty acid-binding protein (FABP) associates with the alpha-synuclein aggregates. Hearttype FABP (hFABP, FABP3) is rich in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D2L), which is abundant in caveolae. We recently demonstrated that mesencephalic neurons require FABP3 and dopamine D2L receptors for the caveolae-mediated alpha-synuclein uptake. Accumulated -synuclein gets fibrillized and tightly co-localizes with FABP3 and dopamine D2L 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 alpha-synuclein propagation and the subsequent aggregate-induced cytotoxicity. We also propose the potential of FABP as a therapeutic target for a-synucleinopathies. (C) 2021 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.

Automated summary

An aging society leads to an increased number of patients with cognitive and movement disorders. This review focuses on the role of FABP3, dopamine receptors, and other FABP family proteins in the process of alpha-synuclein propagation and the subsequent aggregate-induced cytotoxicity, and proposes the potential of FABP as a therapeutic target for alpha-synucleinopathies.