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A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants

Katie J Ryan1,2,3,4, Charles C White1,2,4, Kruti Patel1,2,3,4

  • 1Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Science Translational Medicine
|December 22, 2017
PubMed

Insights

Researchers developed human microglia-like cells to study neurodegenerative diseases. Genetic analysis revealed specific gene variants influencing disease risk and expression, particularly in Parkinson's disease.

Area of Science:

  • Neuroimmunology
  • Genetics
  • Neurodegenerative Diseases

Background:

  • Microglia play a crucial role in neurodegenerative diseases.
  • Studying human microglia in vitro presents significant challenges.
  • Existing models do not fully capture microglial complexity.

Purpose of the Study:

  • To develop a robust in vitro model of human microglia.
  • To investigate the functional impact of genetic variants associated with neurodegenerative diseases.
  • To identify cis-eQTLs in microglia-like cells relevant to Alzheimer's, Parkinson's, and multiple sclerosis.

Main Methods:

  • Development of human monocyte-derived microglia-like (MDMi) cells.
  • Expression quantitative trait locus (eQTL) analysis of 94 disease-associated genes.
  • Validation of genetic variant effects at the protein level and functional assays (phagocytosis).

Main Results:

  • Six loci (CD33, PILRB, NUP160, LRRK2, RGS1, METTL21B) showed cis-eQTLs in MDMi cells.
  • Specific cis-eQTLs were identified in MDMi cells but not in monocytes (PILRB, LRRK2).
  • Risk haplotypes for PILRB and CD33 were validated at the protein level; CD33 risk haplotype impaired phagocytosis.

Conclusions:

  • MDMi cells provide a valuable model for studying human microglia in vitro.
  • Genetic variants associated with neurodegenerative diseases can alter gene expression and function in microglia-like cells.
  • The study implicates altered LRRK2 expression in Parkinson's disease pathogenesis due to a specific SNP.

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