Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

Abstract

Alpha-synuclein (a-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD is characterized by the loss of dopaminergic neuronal cells in the substantia nigra pars compacta and the abnormal accumulation and aggregation of a-Syn in the form of Lewy bodies and Lewy neurites. More precisely, the aggregation of a-Syn is associated with the dysfunctionality and degeneration of neurons in PD. Moreover, mutations in the SNCA gene, which encodes a-Syn, cause familial forms of PD and are the basis of sporadic PD risk. Given the role of the a-Syn protein in the pathology of PD, animal models that reflect the dopaminergic neuronal loss and the widespread and progressive formation of a-Syn aggregates in different areas of the brain constitute a valuable tool. Indeed, animal models of PD are important for understanding the molecular mechanisms of the disease and might contribute to the development and validation of new therapies. In the absence of animal models that faithfully reproduce human PD, in recent years, numerous animal models of PD based on a-Syn have been generated. In this review, we summarize the main features of the a-Syn pre-formed fibrils (PFFs) model and recombinant adenoassociated virus vector (rAAV) mediated a-Syn overexpression models, providing a detailed comparative analysis of both models. Here, we discuss how each model has contributed to our understanding of PD pathology and the advantages and weakness of each of them. Significance: Here, we show that injection of a-Syn PFFs and overexpression of a-Syn mediated by rAAV lead to a different pattern of PD pathology in rodents. First, a-Syn PFFs models trigger the Lewy body-like inclusions formation in brain regions directly interconnected with the injection site, suggesting that there is an inter-neuronal transmission of the a-Syn pathology. In contrast, rAAV-mediated a-Syn overexpression in the brain limits the a-Syn aggregates within the transduced neurons. Second, phosphorylated a-Syn inclusions obtained with rAAV are predominantly nuclear with a punctate appearance that becomes diffuse along the neuronal fibers, whereas a-Syn PFFs models lead to the formation of cytoplasmic aggregates of phosphorylated a-Syn reminiscent of Lewy bodies and Lewy neurites.

The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds

“…It is encoded by the SNCA gene in humans and is mainly expressed in the presynaptic terminals of neurons (Iwai et al, 1995). Endogenous a-syn regulates neurotransmitter release and synaptic vesicle homeostasis through the interaction with synaptic vesicle membranes (Burré et al, 2010;Gó mez-Benito et al, 2020;Mori et al, 2020;Nemani et al, 2010). An imbalance of this a-syn-membrane interaction may induce the formation of a-syn fibrils (Mori et al, 2020).…”

The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds

“…It is encoded by the SNCA gene in humans and is mainly expressed in the presynaptic terminals of neurons 2 . Endogenous α-syn regulates neurotransmitter release and synaptic vesicle homeostasis through the interaction with synaptic vesicle membranes [3][4][5][6] . An imbalance of this α-syn-membrane interaction may induce the formation of αsyn fibrils 6 .…”

Role of SNAREs in Neurodegenerative Diseases

“…PD is normally characterized by the accumulation of misfolded and fibrillary forms of α-syn in surviving neurons, named Lewy Bodies (LBs) and progressive death of dopaminergic neurons in the substantia nigra pars compacta (reviewed in [ 90 ]). Interestingly, the degradation of α-syn is dependent on its phosphorylation state and on the functionality of the ubiquitin-proteasome system and autophagy-lysosomal pathway [ 91 ]. Furthermore, α-syn is spread outside the cell through extracellular vesicles (EVs) and a high amount is found in the CSF and plasma during the early phase of PD [ 92 ].…”