Multiplication of the SNCA locus exacerbates neuronal nuclear aging

Hum Mol Genet. 2019 Feb 1;28(3):407-421. doi: 10.1093/hmg/ddy355.

Abstract

Human-induced Pluripotent Stem Cell (hiPSC)-derived models have advanced the study of neurodegenerative diseases, including Parkinson's disease (PD). While age is the strongest risk factor for these disorders, hiPSC-derived models represent rejuvenated neurons. We developed hiPSC-derived Aged dopaminergic and cholinergic neurons to model PD and related synucleinopathies. Our new method induces aging through a `semi-natural' process, by passaging multiple times at the Neural Precursor Cell stage, prior to final differentiation. Characterization of isogenic hiPSC-derived neurons using heterochromatin and nuclear envelope markers, as well as DNA damage and global DNA methylation, validated our age-inducing method. Next, we compared neurons derived from a patient with SNCA-triplication (SNCA-Tri) and a Control. The SNCA-Tri neurons displayed exacerbated nuclear aging, showing advanced aging signatures already at the Juvenile stage. Noteworthy, the Aged SNCA-Tri neurons showed more α-synuclein aggregates per cell versus the Juvenile. We suggest a link between the effects of aging and SNCA overexpression on neuronal nuclear architecture.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Differentiation
  • Cellular Senescence / genetics
  • Cholinergic Neurons / metabolism
  • Cholinergic Neurons / physiology
  • DNA Damage
  • DNA Methylation
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / physiology
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / physiology
  • Neurons / cytology*
  • Neurons / metabolism
  • Parkinson Disease / genetics*
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / metabolism
  • alpha-Synuclein / physiology

Substances

  • SNCA protein, human
  • alpha-Synuclein