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

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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.

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Acknowledgments

R01 NS42859 from the National Institutes of Health (Bethesda, MD), Parkinson Disease Foundation, and American Academy of Neurology Clinical Research Training Fellowship.

Conflict of interest

The authors report no conflicts of interest.

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Authors and Affiliations

  1. Department of Neurology, College of Physicians and Surgeons, Columbia University, 710 West 168th Street, 3rd Floor, New York, NY, 10032, USA

    Sheng-Han Kuo, Guomei Tang, Elan D. Louis, Ai Yamamoto & David Sulzer

  2. Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Elan D. Louis, Etty Cortes & Jean-Paul G. Vonsattel

  3. GH Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Elan D. Louis, Karen Ma & Rachel Babji

  4. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

    Elan D. Louis

  5. Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY, USA

    Matthew Balatbat, Etty Cortes, Jean-Paul G. Vonsattel, Ai Yamamoto & Phyllis L. Faust

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  1. Sheng-Han Kuo
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401_2013_1108_MOESM1_ESM.docx

Supplemental Fig 1: Lingo-1 peptide block in the cerebellar cortex. Immunohistochemistry with Lingo-1 antibody (a, c) and Lingo-1 antibody with Lingo-1 peptide block (b, d) using DAB (a, b) or dual immunofluorescence with anti-Lingo-1 (Alexa 488, green) and anti-calbindinD28k (Alexa 594, red)(c, d) in consecutive sections (a and b, c and d). The strong Lingo-1 plexus staining by anti-Lingo-1 antibody (a, c) was specifically blocked by Lingo-1 peptide (b, d); note also reduced Lingo-1 immunostaining in the ML (b). Arrows: Lingo-1-positive pinceau. Arrowheads (c, d): PC bodies in consecutive sections. Scale bar: 50 μm. (DOCX 52 kb)

401_2013_1108_MOESM2_ESM.tif

Supplemental Fig 2: Area occupied by Lingo-1 plexus. The Lingo-1 immunostained plexus (a1) was outlined in randomly selected 400X fields and the area measured by Image J software (a2). Lingo-1 pinceau occupied area in ET cases and controls (b). (TIFF 14257 kb)

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Kuo, SH., Tang, G., Louis, E.D. et al. Lingo-1 expression is increased in essential tremor cerebellum and is present in the basket cell pinceau. Acta Neuropathol 125, 879–889 (2013). https://doi.org/10.1007/s00401-013-1108-7

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