TSUKUSHI associate idiopathic normal pressure hydrocephalus with neurodevelopmental disorder in mice. Mus

Idiopathic normal pressure hydrocephalus (iNPH), often observed by cranial enlargement and ventricular expansion, is developed with vomiting, gait disturbance, lack of concentration (Hebb and Cusimano, 2001). Abnormality of neural stem cell (NSC) niche in the LV is known as the reason of iNPH, however the relationship with iNPH is not fully understood (Carter et al., 2012; Ferland et al., 2009; Kahle et al., 2016). We show that Wnt antagonist TSUKUSHI (TSK) deficiency results in neonatal hydrocephalus with neurodevelopmental disorder-like symptoms by altering cell proliferation and differentiation of the NSC niche in mice. We found multiple TSK variants in the genome of hydrocephalus patients and reproduced multiple variant of TSK lost binding activity for the receptor Frizzled-3 and cause hydrocephalus in mice. In addition, transcriptome revealed loss of TSK disturbed profile of Wnt signaling, tight junction and development of ventricular cilia. Finally, we showed TSK protein or Wnt antagonist C59 injection to TSK-KO mice suppress lateral ventricle expansion. These results indicate that TSK modulate lateral ventricle development and TSK is therapeutics candidate for iNPH.