Adeno-Associated Virus Expression of α-Synuclein as a Tool to Model Parkinson’s Disease: Current Understanding and Knowledge Gaps

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the aging population and is characterized by a constellation of motor and non-motor symptoms. The abnormal aggregation and spread of alpha-synuclein (α-syn) is thought to underlie the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc), leading to the development of PD. It is in this context that the use of adeno-associated viruses (AAVs) to express a-syn in the rodent midbrain has become a popular tool to model SNc DA neuron loss during PD. In this review, we summarize results from two decades of experiments using AAV-mediated a-syn expression in rodents to model PD. Specifically, we outline aspects of AAV vectors that are particularly relevant to modeling a-syn dysfunction in rodent models of PD such as changes in striatal neurochemistry, a-syn biochemistry, and PD-related behaviors resulting from AAV-mediated a-syn expression in the midbrain. Finally, we discuss the emerging role of astrocytes in propagating a-syn pathology, and point to future directions for employing AAVs as a tool to better understand how astrocytes contribute to a-syn pathology during the development of PD. We envision that lessons learned from two decades of utilizing AAVs to express a-syn in the rodent brain will enable us to develop an optimized set of parameters for gaining a better understanding of how a-syn leads to the development of PD.