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

Alicia Requena Jimenez1, Naila Naz1, Jaleel A Miyan1

  • 1Faculty of Biology, Medicine & Health, Division of Neuroscience & Experimental Psychology, The University of Manchester, Manchester, UK.

Insights

Depletion of 10-formyl-tetrahydrofolate-dehydrogenase (FDH) in cerebrospinal fluid (CSF) halts brain cell growth in hydrocephalus (HC). FDH regulates folate to control arachnoid cell division, crucial for fluid absorption.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Hydrocephalus (HC) involves cerebrospinal fluid (CSF) imbalance, leading to brain fluid accumulation and pathology.
  • A unique cerebral folate system's role in HC pathophysiology is under investigation.

Purpose of the Study:

  • To investigate the role of 10-formyl-tetrahydrofolate-dehydrogenase (FDH) and the cerebral folate system in hydrocephalus.
  • To determine the impact of CSF folate levels on arachnoid and cortical progenitor cell proliferation in HC.

Main Methods:

  • Tissue culture, immunohistochemistry, in-situ PCR, and RT-PCR were employed.
  • Experiments involved analyzing CSF from hydrocephalic Texas (H-Tx) rats and its effect on cell proliferation.
  • FDH, folate-receptor-alpha (FRα), and folate levels were quantified and manipulated.

Main Results:

  • Depletion of CSF FDH in H-Tx rats correlated with cortical progenitor cell-cycle arrest.
  • In vitro, arachnoid cell proliferation was folate-dependent and exacerbated by HC-CSF with low FDH but high FRα and folate.
  • Adding FDH to HC-CSF normalized aberrant arachnoid cell proliferation, indicating FDH's regulatory role.

Conclusions:

  • Abnormal CSF levels of FDH, FRα, and folate impair cortical cell proliferation in HC.
  • Uncontrolled arachnoid cell division occurs in HC, potentially to enhance fluid absorption, but this mechanism fails.
  • FDH acts as a folate buffer, regulating arachnoid cell proliferation and function in the cerebral folate system.

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