Patient-Derived Induced Pluripotent Stem Cells and Organoids for Modeling Alpha Synuclein Propagation in Parkinson's Disease

Abstract

Parkinson's disease (PD) is an age-associated, progressive neurodegenerative disorder characterized by motor impairment and in some cases cognitive decline. Central to the disease pathogenesis of PD is a small, presynaptic neuronal protein known as alpha synuclein (a-syn), which tends to accumulate and aggregate in PD brains as Lewy bodies or Lewy neurites. Numerous in vitro and in vivo studies confirm that a-syn aggregates can be propagated from diseased to healthy cells, and it has been suggested that preventing the spread of pathogenic a-syn species can slow PD progression. In this review, we summarize the works of recent literature elucidating mechanisms of a-syn propagation, and discussed the advantages in using patient-derived induced pluripotent stem cells (iPSCs) and/or induced neurons to study a-syn transmission.

Keywords: alpha synuclein (α-synuclein); disease modeling; iPSCs; lewy body disease; organoids.

Figure 1

iPSC-derived midbrain cultures as an in vitro model of alpha synuclein transmission. A co-culture model of PD-DA neurons (cells in yellow), WT-GFP neurons (cells in green), and astrocytes (in blue) can be used to track the transfer of pathogenic alpha-synuclein (orange hexagon) between diseased and healthy neurons/astrocytes. PD-DA neurons are derived from the iPSCs of PD patients with their alpha synuclein tagged with a FLAG protein (red rectangle). WT-GFP neurons are derived from the iPSCs of healthy subjects and are constitutively expressing GFP as a reporter–the successful transmission of alpha-synuclein between diseased and healthy neurons can be defined as GFP-expressing cells co-expressing the FLAG signal. Several mechanisms have been postulated to be involved in the propagation of diseased alpha-synuclein to healthy neurons/astrocytes. One mechanism describes that pathogenic alpha synuclein secreted by PD-DA neurons (1a) could interact with various surface proteins on healthy neurons/astrocytes to induce uptake through receptor-mediated endocytosis (1b), for example LAG3 receptor. Furthermore, there are also specialized structures known as tunneling nanotubes (TNTs) between neuron-neuron and neuron-astrocytes that are involved in the spread of alpha synuclein (2).