Open AccessIncreased plasmin-mediated proteolysis of L1CAM in a mouse model of idiopathic normal pressure hydrocephalus
Author(s) -
Deye Yang,
Hongwei Yang,
Gabrielle Luiselli,
Charles Ogagan,
Huijun Dai,
Lucinda Chiu,
Rona S. Carroll,
Mark D. Johnson
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2010528118
Subject(s) - l1 , biology , microbiology and biotechnology , plasmin , medicine , endocrinology , genetics , biochemistry , gene , enzyme
Significance Idiopathic normal pressure hydrocephalus (iNPH) is the most common form of adult-onset hydrocephalus, but its etiology is poorly understood. Symptoms develop in previously normal individuals and include gait difficulty, incontinence, and dementia. We recently reported that 15% of iNPH patients harbor heterozygous loss-of-function deletions in CWH43, which encodes a protein that modifies other cell membrane proteins. Mice harboring CWH43 deletions develop hydrocephalus and gait dysfunction. Mutations affecting the L1CAM adhesion protein cause developmental brain abnormalities and hydrocephalus from birth. Here, we show that CWH43 deletion leads to L1CAM hypoglycosylation, decreased L1CAM association with lipid microdomains, increased plasmin-mediated L1CAM cleavage, and decreased L1CAM expression. Thus, decreased L1CAM expression appears to occur in adult-onset iNPH and congenital hydrocephalus.