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

Stem Cell Reports. 2019 Feb 12;12(2):213-229. doi: 10.1016/j.stemcr.2018.12.011. Epub 2019 Jan 10.

Abstract

Parkinson'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.

Keywords: CRISPR/Cas9; LRRK2; Parkinson's disease; astrocytes; autophagy; disease modeling; iPSC; neurodegeneration; non-cell-autonomous; α-synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytes / cytology*
  • Astrocytes / metabolism
  • Autophagy / physiology
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Coculture Techniques / methods
  • Dopaminergic Neurons / cytology
  • Dopaminergic Neurons / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Mesencephalon / cytology
  • Mesencephalon / metabolism
  • Neuroglia
  • Parkinson Disease / metabolism
  • Parkinson Disease / physiopathology*
  • Phenotype
  • alpha-Synuclein / metabolism

Substances

  • alpha-Synuclein
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2