Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease.

Angelique Di Domenico,Marta Gut,Janani Parameswaran,Armida Faella,Angel Raya,Eduardo Tolosa,Antonella Consiglio,Irene Fernandez-Carasa,Ana Maria Cuervo,Antonio Zorzano,Carles Calatayud,Juan Pablo Muñoz,Isidro Ferrer,Jordi Soriano,Yvonne Richaud-Patin,Giulia Carola,Meritxell Pons-Espinal

doi:10.1016/j.stemcr.2018.12.011

Abstract

SummaryParkinson's disease (PD) is associated with the degeneration of ventral midbrain dopaminergic neurons (vmDAns) and the accumulation of toxic α-synuclein. A non-cell-autonomous contribution, in particular of astrocytes, during PD pathogenesis has been suggested by observational studies, but remains to be experimentally tested. Here, we generated induced pluripotent stem cell-derived astrocytes and neurons from familial mutant LRRK2 G2019S PD patients and healthy individuals. Upon co-culture on top of PD astrocytes, control vmDAns displayed morphological signs of neurodegeneration and abnormal, astrocyte-derived α-synuclein accumulation. Conversely, control astrocytes partially prevented the appearance of disease-related phenotypes in PD vmDAns. We additionally identified dysfunctional chaperone-mediated autophagy (CMA), impaired macroautophagy, and progressive α-synuclein accumulation in PD astrocytes. Finally, chemical enhancement of CMA protected PD astrocytes and vmDAns via the clearance of α-synuclein accumulation. Our findings unveil a crucial non-cell-autonomous contribution of astrocytes during PD pathogenesis, and open the path to exploring novel therapeutic strategies aimed at blocking the pathogenic cross talk between neurons and glial cells.

Highlights

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer’s disease, affecting 7 to 10 million people worldwide (Global Burden of Disease Study Collaborators, 2015)
Astrocyte cultures were successfully established from induced pluripotent stem cell (iPSC) lines from three PD patients carrying the G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene (PD SP06, PD SP12, and PD SP13) and two healthy age-matched controls (Ctrl SP09 and Ctrl SP17)
The astrocytic identity was further confirmed by quantitative RT-PCR of glial fibrillary acidic protein (GFAP) and additional astrocyte-specific genes, including MLC1, SOX9, ALDH1L1, AQP4, DIO2, and SLC4A4, which were expressed in Ctrl and PD astrocytes, and in human primary astrocytes, but not in iPSCs (Figures S1A–S1C)

Summary

Introduction

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer’s disease, affecting 7 to 10 million people worldwide (Global Burden of Disease Study Collaborators, 2015). PD is characterized by a significant loss of ventral midbrain dopaminergic neurons (vmDAns) in the substantia nigra pars compacta. The presence of intracellular protein aggregates of a-synuclein (a-syn) in the surviving vmDAns has been reported in postmortem PD tissue (Greenamyre and Hastings, 2004). Most PD cases are sporadic (85%), but familial mutations are accountable for 15% of patients (Lill, 2016). Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2), causing an autosomal dominant form of PD, account for 5% of familial cases and 2% of sporadic cases (Gilks et al, 2005; Nichols et al, 2005). LRRK2 is a highly complex protein with both GTPase and protein kinase domains involved in several cellular functions, including autophagy (Cookson, 2016; Orenstein et al, 2013; Su et al, 2015)

Results

Discussion

Conclusion