Cellular Models of Alpha-Synuclein Aggregation: What Have We Learned and Implications for Future Study

Abstract

Alpha-synuclein's role in diseases termed "synucleinopathies", including Parkinson's disease, has been well-documented. However, after over 25 years of research, we still do not fully understand the alpha-synuclein protein and its role in disease. In vitro cellular models are some of the most powerful tools that researchers have at their disposal to understand protein function. Advantages include good control over experimental conditions, the possibility for high throughput, and fewer ethical issues when compared to animal models or the attainment of human samples. On the flip side, their major disadvantages are their questionable relevance and lack of a "whole-brain" environment when it comes to modeling human diseases, such as is the case of neurodegenerative disorders. Although now, with the advent of pluripotent stem cells and the ability to create minibrains in a dish, this is changing. With this review, we aim to wade through the recent alpha-synuclein literature to discuss how different cell culture setups (immortalized cell lines, primary neurons, human induced pluripotent stem cells (hiPSCs), blood-brain barrier models, and brain organoids) can help us understand aggregation pathology in Parkinson's and other synucleinopathies.

Keywords: Lewy body; Parkinson’s disease; SH-SY5Y; aggregation; alpha-synuclein; astrocytes; blood–brain barrier; hiPSCs; microglia; mutation; organoid; overexpression; synucleinopathy.

Figure 1

Number of original articles published per year on “alpha-synuclein” starting from 1997 when it was demonstrated that α-syn is involved in PD, up until 2021. Since 2020, over 1000 articles have been published in a year. Data was obtained from Scopus (https://www.scopus.com/, accessed on 10 January 2021). A search was made for the word “alpha-synuclein” within ‘Article title, Abstract, Keywords’. This was further refined to Articles (so as to exclude Reviews and Book Chapters), then the years were narrowed from 1997 to 2021. This generated a total of 11,959 results.

Figure 2

Structural diagram of alpha-synuclein protein. The N-terminal contains an amphiphilic region characterized by apolipoprotein repeat motif. The non-amyloid component (NAC) region is important in the oligomerization and aggregation of α-syn. The C-terminal domain is characterized by acidic residues Glu and Asp and assumes an inherently disordered conformation. Phosphorylation at Ser129 is a classical marker for aggregated α-syn.