The role of age‐associated alpha‐synuclein aggregation in a conditional transgenic mouse model of Parkinson's disease: Implications for Lewy body formation

Parkinson's disease (PD) is a common neurodegenerative disorder that is affecting an increasing number of older adults. Although PD is mostly sporadic, genetic mutations have been found in cohorts of families with a history of familial PD (FPD). The first such mutation linked to FPD causes a point mutation (A53T) in α‐synuclein (α‐syn), a major component of Lewy bodies, which are a classical pathological hallmark of PD. These findings suggest that α‐syn is an important contributor to the development of PD. In our previous study, we developed an adenoviral mouse model of PD and showed that the expression of wild‐type (WT) α‐syn or a mutant form with an increased propensity to aggregate, designated as WT‐CL1 α‐syn, could be used to study how α‐syn aggregation contributes to PD. In this study, we established a transgenic mouse model that conditionally expresses WT or WT‐CL1 α‐syn in dopaminergic (DA) neurons and found that the expression of either WT or WT‐CL1 α‐syn was associated with an age‐dependent degeneration of DA neurons and movement dysfunction. Using this model, we were able to monitor the process of α‐syn aggregate formation and found a correlation between age and the number and sizes of α‐syn aggregates formed. These results provide a potential mechanism by which age‐dependent α‐syn aggregation may lead to the formation of Lewy bodies in PD pathogenesis. Parkinson's disease (PD) is a common neurodegenerative disorder, and recent studies have shown that mutation or abnormal accumulation of α‐synuclein (α‐syn) is associated with PD. In this study, we found that a selective expression of WT (WT‐α‐syn) or a modified form of α‐syn (WT‐α‐ayn‐CL1) which has an increased propensity for aggregation in the dopaminergic neurons could lead to an age‐dependent neurodegeneration. We further found that accumulation of alpha‐syn aggregates in sizes and numbers were age‐associated, suggesting a possible mechanism in the formation of Lewy bodies and neurodegeneration in PD. Cover image for this issue: https://doi.org/10.1111/jnc.15859