α-Synuclein-Based Animal Models of Parkinson's Disease: Challenges and Opportunities in a New Era

Best Practices for Generating and Using Alpha-Synuclein Pre-Formed Fibrils to Model Parkinson’s Disease in Rodents

“…The most common genetic modifications modeled include the autosomal dominant mutations in the genes encoding aSyn [8–9, 14] and leucine-rich repeat kinase 2 (LRRK2) [15–16], and the autosomal recessive mutations in the genes encoding Parkin [17], PTEN-induced putative kinase 1 (PINK1) [18], and DJ-1 [19–21]. Genetically-modified models are advantageous in that they express genetic mutations linked to inherited forms of PD and express the implicated protein at moderate supra-physiological or near-physiological levels for long periods as occurs in the disease, allowing investigators to probe disease-relevant pathways and test therapeutic interventions for familial forms of PD [11–13, 20].…”

“…Similar to toxin models, viral vectors overexpressing aSyn can induce a robust lesion of the nigrostriatal system leading to behavioral phenotypes in rodents and non-human primates using a system that allows spatiotemporal control and the ability to design studies with an internal control [23][23]. In addition, the level of protein overexpression can easily be altered to reduce the level of overexpression to sub-toxic levels or prolong the time before degeneration if desired [14,24–25]. The main drawback of this model, however, is the supra-physiological level of overexpression required for pathology, leading to the question of generalizability between this model and the human condition.…”

Behavioral Phenotyping and Pathological Indicators of Parkinson's Disease in C. elegans Models

“…Rodent models display many of the clinical features of PD such as the loss of dopaminergic neurons (Meredith and Rademacher, 2011; Thiele et al, 2012; Torres and Dunnett, 2012), neurochemical changes in dopamine transmission and signaling, motor dysfunction, and non-motor symptoms including cognitive decline, autonomic dysfunction, depression, and hyposmia (Taylor et al, 2010; Schirinzi et al, 2016). However, these models do not mimic some important pathological hallmarks of the disease (Fleming and Chesselet, 2006; Visanji et al, 2016) such as the gradual neurodegenerative process, gross morphological abnormalities and overt motor alterations (Yue and Lachenmayer, 2011; Ribeiro et al, 2013; Schirinzi et al, 2016). Moreover, gene editing techniques in rodents involve complex experimental design, significant time investment and considerable expense.…”

New Insight into Alzheimer’s Disease via Caspase 3-cleaved Tau: Pathogenic Role in Tau Oligomer Formation and Memory Deficits

“…Compared to normal tau, genetic mutation in or post-translational modification of tau facilitates the formation of tau aggregates. Similar intracellular protein oligomer and aggregate conformers found in other neurodegenerative diseases, such as mutant Huntingtin in Huntington's disease [9,10], Spinocerebellar ataxia type 1 (SCA) in spinocerebellar ataxia [11], alpha-synuclein in Parkinson's disease [12], and TAR DNAbinding protein-43 (TDP-43) in amyotrophic lateral sclerosis [13] are also thought to induce the respective diseases [14]. Therefore, it is important to study the tau species between oligomers and aggregates found in Alzheimer's disease, with particular attention to their role in memory impairment and the loss of synaptic function.…”