MicroRNA alterations in iPSC-derived dopaminergic neurons from Parkinson disease patients

Neurobiol Aging. 2018 Sep;69:283-291. doi: 10.1016/j.neurobiolaging.2018.05.032. Epub 2018 May 31.

Abstract

MicroRNA (miRNA) misregulation in peripheral blood has been linked to Parkinson disease (PD) but its role in the disease progression remains elusive. We performed an explorative genome-wide study of miRNA expression levels in dopaminergic neurons (DAn) from PD patients generated by somatic cell reprogramming and induced pluripotent stem cells differentiation. We quantified expression levels of 377 miRNAs in DAn from 3 sporadic PD patients (sPD), 3 leucine-rich repeat kinase 2-associated PD patients (L2PD) (total 6 PD), and 4 healthy controls. We identified differential expression of 10 miRNA of which 5 were upregulated in PD (miR-9-5p, miR-135a-5p, miR-135b-5p, miR-449a, and miR-449b-5p) and 5 downregulated (miR-141-3p, miR-199a-5p, miR-299-5p, miR-518e-3p, and miR-519a-3p). Changes were similar in sPD and L2PD. Integrative analysis revealed significant correlations between miRNA/mRNA expression. Moreover, upregulation of miR-9-5p and miR-135b-5p was associated with downregulation of transcription factors related to the DNA hypermethylation of enhancer elements in PD DAn (FOXA1 and NR3C1). In summary, miRNA changes are associated with monogenic L2PD and sPD and co-occur with epigenetic changes in DAn from PD patients.

Keywords: Dopaminergic neuron (DAn); Leucine-rich repeat kinase 2 (LRRK2); Parkinson disease (PD); Transcription factor (TF); microRNA (miRNA).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cell Differentiation
  • Dopaminergic Neurons / metabolism*
  • Down-Regulation
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Male
  • MicroRNAs / metabolism*
  • Middle Aged
  • Neural Stem Cells / metabolism
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Up-Regulation

Substances

  • MicroRNAs
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2