Increased plasmin-mediated proteolysis of L1CAM in a mouse model of idiopathic normal pressure hydrocephalus

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.
Idiopathic normal pressure hydrocephalus (iNPH) is a common neurological disorder that is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and dementia. iNPH usually develops after the sixth decade of life in previously asymptomatic individuals. We recently reported that loss-of-function deletions in CWH43 lead to the development of iNPH in a subgroup of patients, but how this occurs is poorly understood. Here, we show that deletions in CWH43 decrease expression of the cell adhesion molecule, L1CAM, in the brains of CWH43 mutant mice and in human HeLa cells harboring a CWH43 deletion. Loss-of-function mutations in L1CAM are a common cause of severe neurodevelopmental defects that include congenital X-linked hydrocephalus. Mechanistically, we find that CWH43 deletion leads to decreased N-glycosylation of L1CAM, decreased association of L1CAM with cell membrane lipid microdomains, increased L1CAM cleavage by plasmin, and increased shedding of cleaved L1CAM in the cerebrospinal fluid. CWH43 deletion also decreased L1CAM nuclear translocation, suggesting decreased L1CAM intracellular signaling. Importantly, the increase in L1CAM cleavage occurred primarily in the ventricular and subventricular zones where brain CWH43 is most highly expressed. Thus, CWH43 deletions may contribute to adult-onset iNPH by selectively downregulating L1CAM in the ventricular and subventricular zone.