Altered folate binding protein expression and folate delivery are associated with congenital hydrocephalus in the hydrocephalic Texas rat

Abstract

Hydrocephalus (HC) is an imbalance in cerebrospinal fluid (CSF) secretion/absorption resulting in fluid accumulation within the brain with consequential pathophysiology. Our research has identified a unique cerebral folate system in which depletion of CSF 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is associated with cortical progenitor cell-cycle arrest in hydrocephalic Texas (H-Tx) rats. We used tissue culture, immunohistochemistry, in-situ PCR and RT-PCR and found that the in-vitro proliferation of arachnoid cells is highly folate-dependent with exacerbated proliferation occurring in hydrocephalic CSF that has low FDH but high folate-receptor-alpha (FRα) and folate. Adding FDH to this CSF prevented aberrant proliferation indicating a regulatory function of FDH on CSF folate concentration. Arachnoid cells have no detectable mRNA for FRα or FDH, but FDH mRNA is found in the choroid plexus (CP) and CSF microvesicles. Co-localization of FDH, FRα and folate suggests important functions of FDH in cerebral folate transport, buffering and function. In conclusion, abnormal CSF levels of FDH, FRα and folate inhibit cortical cell proliferation but allow uncontrolled arachnoid cell division that should increase fluid absorption by increasing the arachnoid although this fails in the hydrocephalic brain. FDH appears to buffer available folate to control arachnoid proliferation and function.

Impaired folate 1-carbon metabolism causes formate-preventable hydrocephalus in glycine decarboxylase–deficient mice

“…Abnormal folate transport to the brain has been proposed to contribute to aqueduct obstruction in the hydrocephalic Texas (H-Tx) rat (23,24). Interestingly, however, hydrocephalus is not commonly described among neurological signs associated with the very low levels of folate in CSF that occur in hereditary folate malabsorption, caused by mutations in SLC46A1 (proton-coupled folate transporter; PCFT) or cerebral folate deficiency, caused by mutations in FOLR1 (folate receptor α; FRα) (25-27).…”

The Role of Single-Nucleotide Polymorphisms in the Function of Candidate Tumor Suppressor ALDH1L1

“…Interestingly, decreased levels of ALDH1L1 in cerebrospinal fluid were linked to neonatal hydrocephalus in a rat model (Cains et al, 2009). Further studies of this model suggested a role for the enzyme in cerebral folate transport and regulation of folate availability in the brain (Naz et al, 2016; Jimenez et al, 2019). In line with such function, it has been also demonstrated that ALDH1L1 protects folate from degradation in zebrafish embryos, which is a defense mechanism against oxidative stress (Chang et al, 2014; Hsiao et al, 2014).…”

Novel therapeutics for hydrocephalus: Insights from animal models

“…The ventricles of these rats remained enlarged, even after the blood pressure was lowered by captopril 89 . Current studies have found that choroid plexus cell death, ependymal injury, impaired glymphatic transport, hemorrhage, and other factors may be involved in the development of hydrocephalus in spontaneously hypertensive rats 17,87,90,91 . Therefore, minocycline is a promising drug for the treatment of hydrocephalus and related tissue damage.…”

“…To unveil the pathogenesis of brain damage in hydrocephalus and develop more effective nonsurgical treatments, researchers have developed different animal models such as intraventricular injection of blood or kaolin to induce hydrocephalus in rats 14,15 . At the same time, some congenital hydrocephalus models characterized by aqueduct stenosis, ependymal stripping, and astrocytes activation have also been applied 16,17 . Although animal models cannot fully simulate human body condition, they still play important roles in hydrocephalus research.…”