It has been suggested that aggregation of alpha-synuclein (alpha-syn) into oligomers leads to neurodegeneration in Parkinson's disease (PD), but intravenous immunoglobulin (IVIG) which contains antibodies against alpha-syn monomers and oligomers fails to treat PD mouse model. The reason may be because IVIG contains much low level of antibodies against alpha-syn, and of which only a small part can penetrate the blood-brain barrier, resulting in an extremely low level of effective antibodies in the brain, and limiting the beneficial effect of IVIG on PD mice. Here, we first isolated naturally occurring autoantibodies against alpha-syn (NAbs-alpha-syn) from IVIG. Our further investigation results showed that NAbs-alpha-syn inhibited alpha-syn aggregation and attenuated alpha-syn-induced cytotoxicity in vitro. Compared with vehicles, NAbs-alpha-syn significantly attenuated the memory and motor deficits by reducing the levels of soluble alpha-syn, total human alpha-syn and alpha-syn oligomers, decreasing the intracellular P-alpha-syn(ser129) deposits and axonal pathology, inhibiting the microgliosis and astrogliosis, as well as the production of proinflammatory cytokines, increasing the levels of PSD95, synaptophysin and TH in the brain of A53T transgenic mice. These findings suggest that NAbs-alpha-syn overcomes the deficiency of IVIG and exhibits a promising therapeutic potential for the treatment of PD.