Differential expression of c-Ret in motor neurons versus non-neuronal cells is linked to the pathogenesis of ALS

Lab Invest. 2011 Mar;91(3):342-52. doi: 10.1038/labinvest.2010.203. Epub 2011 Jan 31.


Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by selective degeneration of motor neurons throughout the central nervous systems. Non-cell autonomous damage induced by glial cells is linked to the selective susceptibility of motor neurons in ALS, but the mechanisms underlying this phenomenon are not known. We found that the expression of non-phosphorylated and phosphorylated forms (tyrosine (Tyr) residue 905, 1016, and 1062) of c-Ret, a member of the glial cell line-derived neurotrophic factor (GDNF) receptor, are altered in motor neurons of the lumbar spinal cord in ALS transgenic (G93A) mice and ALS (G93A) cell line models. Phosphorylated forms of c-Ret were colocalized with neurofilament aggregates in motor neurons of ALS mice. Consistent with the in vivo data, levels of non-phosphorylated and phosphorylated c-Ret (Tyr 905, 1016, and 1062) were decreased by oxidative stress in motor neuronal cells (NSC-34). Non-phosphorylated and phosphorylated forms of c-Ret immunoreactivity were markedly elevated in active microglia of ALS mice. Our findings suggest that constitutive oxidative stress modulates c-Ret function, thereby reducing GDNF signaling in motor neurons. Furthermore, the induction of c-Ret expression in microglia may contribute to non-cell autonomous cell death of motor neurons by available GDNF in ALS.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Astrocytes / metabolism
  • Cell Line
  • Gene Expression Regulation
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / genetics
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism
  • Humans
  • Lumbar Vertebrae
  • Mice
  • Mice, Transgenic
  • Microglia / metabolism
  • Motor Neurons / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Organ Specificity
  • Oxidative Stress
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / metabolism*
  • RNA, Messenger / metabolism
  • Spinal Cord / metabolism
  • Spinal Cord / pathology


  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Ret protein, mouse