The Impact of SNCA Variations and Its Product Alpha-Synuclein on Non-Motor Features of Parkinson's Disease

Abstract

Parkinson's disease (PD) is a common and progressive neurodegenerative disease, caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which is clinically characterized by a constellation of motor and non-motor manifestations. The latter include hyposmia, constipation, depression, pain and, in later stages, cognitive decline and dysautonomia. The main pathological features of PD are neuronal loss and consequent accumulation of Lewy bodies (LB) in the surviving neurons. Alpha-synuclein (α-syn) is the main component of LB, and α-syn aggregation and accumulation perpetuate neuronal degeneration. Mutations in the α-syn gene (SNCA) were the first genetic cause of PD to be identified. Generally, patients carrying SNCA mutations present early-onset parkinsonism with severe and early non-motor symptoms, including cognitive decline. Several SNCA polymorphisms were also identified, and some of them showed association with non-motor manifestations. The functional role of these polymorphisms is only partially understood. In this review we explore the contribution of SNCA and its product, α-syn, in predisposing to the non-motor manifestations of PD.

Keywords: Parkinson’s disease; alpha-synuclein; non-motor symptoms.

Figure 1

The impact of SNCA variation in the development of non-motor symptoms in Parkinson’s disease. Gene mutations and polymorphisms generate different SNCA transcripts. A-syn accumulates in the Lewy bodies or circulates in body fluids. Its interaction with immune cells drives a pro-inflammatory response ultimately favoring cell death. A-syn overproduction, spreading and deposition contribute to motor and non-motor manifestations.