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

Yong Hui Koh,Shi-Yan Ng,Li Yi Tan

doi:10.3389/fncel.2018.00413

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.

Highlights

Parkinson’s disease (PD) is a progressive and chronic neurological disorder and the second most prevalent neurodegenerative disease after Alzheimer’s disease, affecting an estimated seven to ten million people worldwide
Mutations in several genes are each associated with the occurrence of PD, including alpha synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), and other autosomal recessive mutations in genes such as Parkin (PARK2), PTEN-induced putative kinase 1 (PINK1) and Protein/nucleic acid deglycase DJ-1 (PARK7), and has been extensively reviewed in Klein and Westenberger (2012)
It was demonstrated that mutant PINK1 and Parkin DA neurons had significantly more insoluble a-syn protein, indicative of aggregated a-syn. These studies have proven that important cellular features of PD are recapitulated in induced pluripotent stem cells (iPSCs)-derived neurons, similar to what has been observed for other neurodegenerative diseases

Summary

INTRODUCTION

Parkinson’s disease (PD) is a progressive and chronic neurological disorder and the second most prevalent neurodegenerative disease after Alzheimer’s disease, affecting an estimated seven to ten million people worldwide. These methods made use of the knowledge on developmental patterning to efficiently differentiate iPSCs into midbrain-regionalized floorplate progenitor cells (Fasano et al, 2010; Kirkeby and Parmar, 2012) using chemical inhibitors of SMAD signaling (achieved by LDN-193189 and SB431542), early high-dose Sonic Hedgehog (SHH) pathway agonists (such as Purmorphamine or recombinant SHH) and partial glycogen synthase kinase (GSK) inhibitors/Wnt activation (by CHIR99021) (Cooper et al, 2010; Devine et al, 2011; Kriks et al, 2011; Kirkeby et al, 2012) This revised strategy produces midbrain DA neurons that expresses the specific forehead box protein A2 (FOXA2) and LIM Homeobox Transcription Factor 1 Alpha (LMX1A) markers and demonstrates efficient dopamine release in vitro (Kirkeby et al, 2012) and in vivo after transplantation (Kriks et al, 2011).

Methods

Human iDAN

Findings

CONCLUDING REMARKS