Novel DNA Aptamers for Parkinson's Disease Treatment Inhibit alpha-Synuclein Aggregation and Facilitate its Degradation

Parkinson's disease (PD) is one of the most prevalent forms of synucleinopathies, and it is characterized neuropathologically by the presence of intracellular inclusions composed primarily of the protein alpha-synudein (alpha-syn) in neurons. The previous immunotherapy targeting the alpha-syn in PD models with monoclonal antibodies has established alpha-syn protein as an effective target for neuronal cell death. However, due to the essential weaknesses of antibody and the unique features of aptamers, the aptamers could represent a promising alternative to the currently used antibodies in immunotherapy for PD. In this study, the purified human alpha-syn was used as the target for in vitro selection of aptamers using systematic evolution by exponential enrichment. This resulted in the identification of two 58-base DNA aptamers with a high binding affinity and good specificity to the alpha-syn, with K-D values in the nanomolar range. Both aptamers could effectively reduce alpha-syn aggregation in vitro and in cells and target the alpha-syn to intracellular degradation through the lysosomal pathway. These effects consequently rescued the mitochondrial dysfunction and cellular defects caused by alpha-syn overexpression. To our knowledge, this is the first study to employ aptamers to block the aberrant cellular effects of the overexpressed alpha-syn in cells.