2. Academic Validation
  3. Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis

Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis

  • Nat Med. 2016 Apr;22(4):397-403. doi: 10.1038/nm.4052.
SungWon Song # 1 2,  Carlos J Miranda # 1,  Lyndsey Braun 1,  Kathrin Meyer 1,  Ashley E Frakes 1 3,  Laura Ferraiuolo 1,  Shibi Likhite 1 2,  Adam K Bevan 1 3,  Kevin D Foust 1 4,  Michael J McConnell 5,  Christopher M Walker 6 7,  Brian K Kaspar 1 2 3 4 7
Affiliations

Affiliations

  • 1 Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
  • 2 Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA.
  • 3 Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio, USA.
  • 4 Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA.
  • 5 Dept. of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
  • 6 Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
  • 7 Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, USA.
  • # Contributed equally.
PMID: 26928464 DOI: 10.1038/nm.4052
Abstract

Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non-cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte-mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity.

Figures