The Role of alpha-Synuclein in the Regulation of Serotonin System: Physiological and Pathological Features

In patients affected by Parkinson's disease (PD), up to 50% of them experience cognitive changes, and psychiatric disturbances, such as anxiety and depression, often precede the onset of motor symptoms and have a negative impact on their quality of life. Pathologically, PD is characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of intracellular inclusions, called Lewy bodies and Lewy neurites, composed mostly of alpha-synuclein (alpha-Syn). Much of PD research has focused on the role of alpha-Syn aggregates in the degeneration of SNc DA neurons due to the impact of striatal DA deficits on classical motor phenotypes. However, abundant Lewy pathology is also found in other brain regions including the midbrain raphe nuclei, which may contribute to non-motor symptoms. Indeed, dysfunction of the serotonergic (5-HT) system, which regulates mood and emotional pathways, occurs during the premotor phase of PD. However, little is known about the functional consequences of alpha-Syn inclusions in this neuronal population other than DA neurons. Here, we provide an overview of the current knowledge of alpha-Syn and its role in regulating the 5-HT function in health and disease. Understanding the relative contributions to alpha-Syn-linked alterations in the 5-HT system may provide a basis for identifying PD patients at risk for developing depression and could lead to a more targeted therapeutic approach.