Abstract
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.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting 1-2% of the population over 65 years
We provide a detailed account of the observed differences in published studies, along with an informed perspective on how one could approach the use of adenoassociated viruses (AAVs) to model PD in rodents
While we focus on AAV-mediated a-syn models in this review, the use of other viral vectors in rodents have enabled an understanding of a-syn pathology
Summary
The first step towards implicating a-syn in PD pathogenesis was the identification of a case of familial PD due to triplication of the SNCA gene that codes for asyn [10]. These findings are similar to previous studies in patients with PD showing an initial degeneration of DA axons in the striatum [27], and relates to an increased risk of PD in humans with DAT mutations [28] This suggests that AAV-mediated a-syn expression in the rodent SNc reliably models clinical aspects of PD related to fluctuations in striatal dopamine. A-syn degradation is mediated by the ubiquitin-proteasome system and the autophagy-lysosomal system; recent studies have revealed damages to these systems that may encourage a-syn aggregation [83, 84, 107, 108] Taken together, these reports suggest diverse roles for asyn in subcellular function with the potential for abnormal a-syn to exert global pathological effects on neuronal physiology. Understanding how these mechanisms affect PD pathogenesis will greatly enhance our knowledge of PD, and neurodegeneration in general
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