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

Abstract

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.

Exploration of the Core Pathways and Potential Targets of Luteolin Treatment on Late-Onset Depression Based on Cerebrospinal Fluid Proteomics

“…Neural cell adhesion molecule L1 (L1CAM) plays an essential role in neural development, regulating processes such as neurite growth, cell migration, neuronal survival, and synaptic plasticity [ 56 ]. In humans, L1CAM mutations may cause severe neurodevelopmental defects [ 57 ]. DCC is expressed on axons and growth spines, and is also the cell surface receptor for Netrin-1.…”

Advances in brain barriers and brain fluids research in 2021: great progress in a time of adversity

“…However, Yang et al [ 44 ] have now identified loss-of-function mutations in the gene CWH43 in 15% of iNPH patients. Yang et al [ 124 ] examined the mechanisms involved and found CWH43 deletions cause downregulation in the cell adhesion molecule L1CAM selectively in the ventricular and subventricular zones. It is known that mutations in L1CAM are a cause of X-linked congenital hydrocephalus [ 125 ].…”

The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression

“…Plasmin regulates fibrinolysis, the activation of growth factors, activation of MMPs, ECM degradation, hormone processing, and activation of factor V, factor VIII, factor X, and protease-activated receptors (PARs). Plasmin is associated with multiple cell functions, cytokine production, apoptosis, and tissue remodeling, as well as inflammation through various mechanisms ( Figure 2 ) [ 11 , 26 , 27 , 28 , 29 , 30 , 31 ]. In contrast, uPA and uPAR interact with transmembrane proteins, such as integrins, and regulate cell growth, migration, differentiation, and adhesion [ 32 , 33 , 34 , 35 , 36 ].…”