Explore the Role of C-Terminally Truncated Alphasynuclein in Parkinson's Disease and Dementia with Lewy Bodies Pathogenesis

Several studies show that C-terminal truncation promotes ?-Synuclein (?-syn) aggregation and thus toxicity. While, C-terminally truncated ?-syn at aa122 (?-syn 122) was found in brains lysates of both DLB and PD patients, no studies have been conducted to understand the role of this truncated ?-syn in the pathogenesis of PD or DLB. The distinct difference in the amount of truncated ?-syn found in DLB and PD patients compared to healthy controls suggests that the ratio of truncated versus full-length ?-syn could be useful in DLB and PD diagnosis. However, as of yet, there are no monoclonal antibodies (mAbs) specific for ?-syn 122. We report here the generation and characterization of novel mAbs that specifically recognize ?-syn 122; D2A1 and C12A6. Western blot analysis showed the specificity of both mAbs towards ?-syn 122. The affinity of both mAbs was determined via indirect ELISA, with C12A6 having the highest affinity. Cross-reactivity to ?-syn 121, ?- syn 123 and ?-syn 140 was tested by western blot and indirect ELISA, and the results showed both D2A1 and C12A6 are specific towards ?-syn 122. Moreover, two ?-syn 122 specific ELISAs were also developed using C12A6 and D2A1, with low detection levels. While western blot analysis of DLB brain lysates showed no traces of ?-syn 122 when probed with D2A1 or C12A6, IHC staining of the Nucleus Basalis of Meynert (NBM) and Amygdala using C12A6 or D2A1 showed Lewy body pathology in both regions. Our novel mAbs were found to be specific for ?-syn-122 and hold the potential for biomarker development in either diagnostic or therapeutic settings as well as offering a better understanding of PD and DLB pathogenesis.