[Development of therapeutic peptides for Lewy body diseases preventing α-synuclein propagation]

With the advent of a super-aging society, overcoming age-related neurological diseases and developing fundamental therapeutic agents are urgent issues. In Lewy body diseases such as Parkinson's disease and dementia with Lewy bodies, the accumulation and aggregation of α-synuclein in the neuronal cells, called Lewy bodies, are known as pathological features. Intracellular accumulation of the causative protein α-synuclein in the central nervous system requires an uptake process into neurons. Type 3 fatty acid-binding protein (FABP3) is highly expressed in dopaminergic neurons and has the ability to bind dopamine receptors, particularly dopamine D2 long type (D2L) receptors, which are abundantly localized on caveolae structures in the plasma membrane. We found that dopaminergic neurons do not take up α-synuclein in FABP3 knockout or D2L receptor-selective knockout mice. Next, we found that the C-terminal deletion of α-synuclein reduces the uptake ability. α-Synuclein has a FABP3 binding site in its C-terminal region. On this point, exposure to the C-terminal peptide reduced α-synuclein uptake into dopaminergic neurons. Based on these findings, this article describes the unique mechanism of the propagation and uptake process of α-synuclein, focusing on the physiological significance of FABP3 and dopamine D2 receptors. Additionally, we will review the development status of therapeutic peptide candidates for Lewy body diseases, and then discuss the novel pathogenic mechanism of Lewy body disease as well as the potential of fundamental therapeutics targeting the uptake process of α-synuclein.