Synuclein targeting therapies for Lewy body diseases

Abstract

Parkinson disease (PD) belongs to a family of disorders called Lewy body disease (LBD), which is pathologically characterized by the appearance of intracellular inclusions (Lewy bodies ; LBs) in neurons that are composed mainly of misfolded α–synuclein (αS). Based on the concept of “proteinopathy”, which attributes the cause of a disease to a single molecule, LBD is included in the higher concept of “synucleinopathy”. Although αS is a small protein that does not have a distinct structure in its physiological state, it will aggregate and exert toxicity due to abnormal folding (misfolding) by gene mutation/duplication or a variety of physicochemical stress. For this reason, many of the disease–modifying therapies for LBD/synucleinopathies have been developed with a focus on reducing or removing abnormally aggregated αS. In this paper, I will explain the disease–modifying therapies targeting αS protein for synucleinopathies, focusing on immunotherapy and aggregation inhibitors, and discuss future issues.