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

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 adenoassociated 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 AAVmediated 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.

Impact of aging on animal models of Parkinson's disease

“…Modeling of CNS pathology has been pursued using different disease modeling strategies: (1) by artificial induction of dopamine deficit through delivery of a neurotoxin, (2) by viral-mediated local overexpression of asyn, (3) through induction of artificial asyn pathology by delivery of different aggregated forms of asyn (also called fibrils) in the brain, or (4) by using transgenic models characterized by elevated human asyn expression under specific promoters of wide or limited expression in the rodent (Dawson et al, 2018 ; Huntington and Srinivasan, 2021 ). CNS aggregate pathology has also been observed in other less common transgenic models, such as those that aim to induce PD by elimination of mitochondrial function (e.g., MitoPark) (Ekstrand and Galter, 2009 ).…”

“…Importantly, differences in CNS-sensitivity to a neurotoxin (Song et al, 2015 ) or viral-mediated mediated overexpression of asyn (Huntington and Srinivasan, 2021 ) have been observed across different strains, even when not genetically engineered, and these differences might be magnified when working with aged animals. More studies in different strains need to be done to assess the effect of aging on multiple features of PD pathogenesis.…”

Genetically modified animal models of hereditary diseases for testing of gene-directed therapy

“…Transgene delivery using viral vectors has become an alternative approach for creating models for human diseases in rats, pigs, and non-human primates. Among other viruses, AAV vectors have proven to be an ideal tool for modeling severe neurological and neuromuscular disorders due to high tropism to neuronal tissues, skeletal and cardiac muscles (Duque et al 2015;Huntington and Srinivasan 2021).…”

A Focus on Astrocyte Contribution to Parkinson’s Disease Etiology

“…Astrocytes also possess a plethora of spontaneous Ca ++ signals that regulate diverse signaling pathways that could act in an autocrine manner to modulate nearby cells [ 134 , 135 ]. In addition, increased levels of Ca ++ ER and altered mitochondrial functions are described in PD patients, which, in turn, will worsen the redox status, thus impairing the antioxidant support and lactate shuttle to neurons.…”