Lingo-1 expression is increased in essential tremor cerebellum and is present in the basket cell pinceau

Acta Neuropathol. 2013 Jun;125(6):879-89. doi: 10.1007/s00401-013-1108-7. Epub 2013 Mar 31.

Abstract

The Lingo-1 sequence variant has been associated with essential tremor (ET) in several genome-wide association studies. However, the role that Lingo-1 might play in pathogenesis of ET is not understood. Since Lingo-1 protein is a negative regulator of axonal regeneration and neurite outgrowth, it could contribute to Purkinje cell (PC) or basket cell axonal pathology observed in postmortem studies of ET brains. In this study, we used Western blotting and immunohistochemistry to examine Lingo-1 protein in ET vs. control brains. In Western blots, Lingo-1 protein expression level was significantly increased in cerebellar cortex (1.56 ± 0.46 in ET cases vs. 0.99 ± 0.20 in controls, p = 0.002), but was similar in the occipital cortex (p = 1.00) of ET cases vs. controls. Lingo-1 immunohistochemistry in cerebellum revealed that Lingo-1 was enriched in the distal axonal processes of basket cells, which formed a "pinceau" structure around the PC axon initial segment (AIS). We found that some Lingo-1-positive pinceau had abnormally elongated processes, targeting PC axon segments distal to the AIS. In ET cases, the percentage of Lingo-1-positive pinceau that were ≥30 or ≥40 μm in length was increased 2.4- to 4.1-fold, respectively, vs. pinceau seen in control brains (p < 0.0001). Elongated Lingo-1-positive pinceau strongly correlated with number of PC axonal torpedoes and a rating of basket cell axonal pathology. The increased cerebellar Lingo-1 expression and elongated Lingo-1-positive pinceau processes could contribute to the abnormal PC and basket cell axonal pathology and cerebellar dysfunction observed in ET.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Axons / metabolism*
  • Axons / pathology
  • Case-Control Studies
  • Cerebellum / metabolism*
  • Cerebellum / pathology
  • Essential Tremor / etiology
  • Essential Tremor / metabolism*
  • Essential Tremor / pathology*
  • Female
  • Humans
  • Male
  • Membrane Proteins / metabolism*
  • Middle Aged
  • Nerve Tissue Proteins / metabolism*
  • Occipital Lobe / metabolism
  • Occipital Lobe / pathology

Substances

  • LINGO1 protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins