Advances in modelling alpha-synuclein-induced Parkinson’s diseases in rodents: Virus-based models versus inoculation of exogenous preformed toxic species

Abstract

Aggregates of alpha-synuclein (αSyn) have been described in Parkinson's disease (PD) patients, and recent evidence has suggested that the most toxic αSyn species in PD are small soluble aggregates including oligomers, prefibrils, protofibrils. The physiological function of αSyn is still highly debated, with a possible role in synaptic vesicle trafficking and release at the presynaptic compartment, and in the regulation of gene expression in the nucleus. Emerging evidence indicate that most of αSyn functions are related with the crucial ability to bind biological membranes, which is associated with structural conversion from a disordered monomer to an α-helical enriched structure. Conformational properties of αSyn can be modulated by a number of factors including post-translational modifications, gene duplication and triplication-driven overexpression, single point mutations, environmental changes, which affect membrane binding and the protein propensity to aggregate in toxic species. The recognized toxic role of αSyn in PD has laid the rational for purposing of αSyn-based, neuropathologically relevant preclinical models of PD. Different approaches have led to the establishment of transgenic models, viral vector-based models, and more recently models based on the intracerebral inoculation of exogenous αSyn preformed fibrils/oligomers. Here, we overview and compare viral vector-based models of αSyn overexpression and models obtained by direct intracerebral infusion of in vitro preformed αSyn species. The advantages and pitfalls associated with these different approaches are discussed.

The proSAAS chaperone provides neuroprotection and attenuates transsynaptic α–synuclein spread in rodent models of Parkinson’s disease

“…The data presented here showing that proSAAS exerts strong protection from aSyn-induced nigro-striatal DA tract degeneration provide the first in vivo evidence of the potential utility of this chaperone as a therapeutic target for PD. AAV-mediated overexpression of human wildtype aSyn unilaterally in the rat SNc produced a robust progressive motor asymmetry over an 8-week period accompanied by significant loss of TH-positive nigral cells and TH-positive striatal terminals measured post-mortem, consistent with previous reports describing similar viral-mediated aSyn models (reviewed in (36)). All three of these measures of aSyn toxicity were profoundly blunted by nigral co-injection of proSAAS-expressing lentivirus.…”

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

“…Apart from the pre-synaptic terminal, potent membrane binding capabilities of a-syn have also been identified in organelles such as mitochondria [38,52,93,94], the endoplasmic reticulum [95,96], the Golgi apparatus [97][98][99] and the nucleus [100]. Multiple forms of a-syn disrupt protein synthesis and degradation pathways, restrict intracellular calcium handling, increase oxidative stress, and impair phagocytic activity [52,101].…”

“…The use of oligomers or PFFs, either injected into the brain [71,140,141], or into the gut [76,142] is a second tool that has recently gained traction and is increasing our understanding of the nature of a-syn spread within the brain. PFFs cause robust DA cell death and show extensive spread of a-syn pathology across brain regions [100,143,144]. Ser-129 phosphorylation of endogenous a-syn in response to extracellular a-syn fibrils exerts profound effects on the ability of a-syn to form toxic aggregates [143], and may be of particular relevance to the spread of a-syn pathology across brain regions.…”

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders

“…For neuropsychiatric disorders, such as schizophrenia, common symptoms such as paranoid delusions and auditory hallucinations are uniquely human and make interpretation of results acquired from animal models particularly challenging (Canetta and Kellendonk, 2018). Although imperfect, there are multiple available models of schizophrenia (Winship et al, 2019), depression (Planchez et al, 2019), and other neuropsychiatric (Nestler and Hyman, 2010) as well as neurodegenerative disorders (Dawson et al, 2018;Carta et al, 2020) that, to varying degrees, possess face validity (observed characteristics/symptoms that have clinical correlates in the human patient population), construct validity (key neurobiological/pathological bases of the human disorder), and/or predictive validity (expected pharmacological response to efficacious drugs currently used to treat the human disorder). Each animal model has its advantages and caveats (Fisher and Bannerman, 2019), and evaluation of hypotheses as well as potential drugs across models undoubtedly provides better predictive value for translation to human studies, particularly when repurposed drugs (such as IMiDs) are evaluated at a clinically translatable dose (Becker and Greig, 2010;Seeman et al, 2019).…”