Synucleinopathies are a group of neurodegenerative diseases that share a common 
pathological lesion of intracellular protein inclusions largely composed by 
aggregates of alpha-synuclein protein. Accumulating evidence, including genome 
wide association studies, has implicated alpha-synuclein (SNCA) gene in the 
etiology of synucleinopathies. However, the precise variants within SNCA gene 
that contribute to the sporadic forms of Parkinson's disease (PD), dementia with 
Lewy bodies (DLB), multiple system atrophy (MSA), and other synucleinopathies 
and their molecular mechanisms of action remain elusive. It has been suggested 
that SNCA expression levels are critical for the development of these diseases. 
Here, we review several model systems that have been developed to advance the 
understanding of the role of SNCA expression levels in the etiology of 
synucleinopathies. We also describe different molecular mechanisms that regulate 
SNCA gene expression and discuss possible strategies for SNCA down-regulation as 
means for therapeutic approaches. Finally, we highlight some examples that 
underscore the relationships between the genetic association findings and the 
regulatory mechanisms of SNCA expression, which suggest that genetic variability 
in SNCA locus is directly responsible, at least in part, to the changes in gene 
expression and explain the reported associations of SNCA with synucleinopathies. 
Future studies utilizing induced pluripotent stem cells (iPSCs)-derived neuronal 
lines and genome editing by CRISPR/Cas9, will allow us to validate, 
characterize, and manipulate the effects of particular cis-genetic variants on 
SNCA expression. Moreover, this model system will enable us to compare different 
neuronal and glial lineages involved in synucleinopathies representing an 
attractive strategy to elucidate-common and specific-SNCA-genetic variants, 
regulatory mechanisms, and vulnerable expression levels underlying 
synucleinopathy spectrum disorders. This forthcoming knowledge will support the 
development of precision medicine for synucleinopathies.