Genetic and molecular mechanisms of hydrocephalus

Abstract

Hydrocephalus is a neurological condition caused by aberrant circulation and/or obstructed cerebrospinal fluid (CSF) flow after cerebral ventricle abnormal dilatation. In the past 50 years, the diagnosis and treatment of hydrocephalus have remained understudied and underreported, and little progress has been made with respect to prevention or treatment. Further research on the pathogenesis of hydrocephalus is essential for developing new diagnostic, preventive, and therapeutic strategies. Various genetic and molecular abnormalities contribute to the mechanisms of hydrocephalus, including gene deletions or mutations, the activation of cellular inflammatory signaling pathways, alterations in water channel proteins, and disruptions in iron metabolism. Several studies have demonstrated that modulating the expression of key proteins, including TGF-β, VEGF, Wnt, AQP, NF-κB, and NKCC, can significantly influence the onset and progression of hydrocephalus. This review summarizes and discusses key mechanisms that may be involved in the pathogenesis of hydrocephalus at both the genetic and molecular levels. While obstructive hydrocephalus can often be addressed by removing the obstruction, most cases require treatment strategies that involve merely slowing disease progression by correcting CSF circulation patterns. There have been few new research breakthroughs in the prevention and treatment of hydrocephalus.

Keywords: animal model; cerebrospinal fluid; genetic abnormality; hydrocephalus; molecular changes.

Figure 1

The canonical and non-canonical Smad signaling pathways induced by TGF-β. In the canonical Smad signaling pathway, TGF-β phosphorylates TGF-βRII, which recruits and phosphorylates TGF-βRI. The activated TGF-βRI subsequently phosphorylates Smad2 and Smad3 proteins. These activated Smad2 and Smad3 proteins then recruit Smad4 to form a complex, which translocates into the nucleus. Within the nucleus, the Smad complex interacts with specific DNA sequences and other transcription factors to promote the transcription and expression of target genes, such as CTGF (Connective Tissue Growth Factor). In the subarachnoid space, CTGF contributes to pia mater fibrosis by promoting the synthesis and deposition of extracellular matrix components. In the non-canonical Smad signaling pathway, the activated TGF-βRI/II complex can further activate Cdc42/Rac1, which in turn activates downstream factors such as the P38 and PAK2 signaling pathways.

Figure 2

VEGF signaling pathway. Upon binding to its receptor VEGFR-2 on the surface of vascular endothelial cells, VEGF first activates Src kinase, which subsequently phosphorylates and activates Vav2. This activation facilitates the conversion of Rac from its GDP-bound inactive state to its GTP-bound active state. Activated Rac further activates PAK (p21-activated kinase). PAK, or alternatively the activated Src kinase, phosphorylates VE-cadherin (Vascular Endothelial Cadherin), allowing β-catenin to bind to its tail. This phosphorylation mediates VE-cadherin internalization, resulting in a “fenestration effect,” which contributes to the development of hydrocephalus. In addition, activated Src kinase can also mediate the PI3K/AKT/mTOR signaling pathway, initiating a series of downstream cascade reactions.

Figure 3

Wnt/β-catenin and NF-κB signaling pathways. Wnt/β-catenin signaling pathway: When Wnt ligands bind to the Frizzled receptor on the membrane of astrocytes, they activate DSH (Disheveled) protein, initiating downstream signaling. DSH inhibits GSK-3β (glycogen synthase kinase-3β) activity, preventing β-catenin phosphorylation. This leads to the accumulation of β-catenin in the cytoplasm, allowing it to translocate to the nucleus, where it binds to transcription factors such as TCF/LEF, regulating gene expression and interfering with CSF circulation and absorption, which contributes to hydrocephalus. Additionally, activated DSH can activate Rac, which further activates the JNK signaling pathway, affecting CSF homeostasis. NF-κB signaling pathway: TNF-α binds to the TNFR1 receptor, directly activating NF-κB signaling; TLR4 recognizes endogenous or exogenous ligands, activating NF-κB through the MyD88-dependent pathway. AMPK activation, caused by cellular energy imbalance, stimulates SIRT1, which subsequently activates NF-κB signaling. IKK2 activation can also trigger NF-κB signaling. Activated NF-κB regulates downstream PI3K/AKT signaling, upregulating TNF-α, forming a positive feedback loop that exacerbates inflammation and further contributes to hydrocephalus development.

Figure 4

Activation of Na⁺/K⁺/2Cl cotransporter. Activated NF-κB initiates a signaling cascade that eventually activates SPAK, which phosphorylates and activates NKCC1, resulting in excessive CSF secretion and contributing to hydrocephalus. Moreover, activated NF-κB also influences NKCC1 activity by modulating the NLRP3 inflammasome, leading to abnormal CSF secretion and the promotion of hydrocephalus. Serum lipid LPA directly acts on TRPV4, mediating Ca²⁺ influx, which regulates the WNK-SPAK-mediated phosphorylation of NKCC1. This results in an increased CSF secretion rate and ventricular enlargement.