Mary C. Wallingford1, Jia Jun Chia1, Elizabeth M. Leaf1, Suhaib Borgeia2,3, Nicholas W. Chavkin1, Chenphop Sawangmake4, Kenneth I. Marro5, Timothy C. Cox2,3, Mei Y. Speer1, Cecilia M. Giachelli1
1Department of Bioengineering, University of Washington, Seattle, WA
2Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute Seattle WA
3Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute Seattle WA; Department of Pediatrics University of Washington Seattle WA
4Department of Pharmacology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
5Department of Radiology, University of Washington, Seattle, WA
Tóm tắt
AbstractIdiopathic basal ganglia calcification is a brain calcification disorder that has been genetically linked to autosomal dominant mutations in the sodium‐dependent phosphate co‐transporter, SLC20A2. The mechanisms whereby deficiency of Slc20a2 leads to basal ganglion calcification are unknown. In the mouse brain, we found that Slc20a2 was expressed in tissues that produce and/or regulate cerebrospinal fluid, including choroid plexus, ependyma and arteriolar smooth muscle cells. Haploinsufficient Slc20a2 +/− mice developed age‐dependent basal ganglia calcification that formed in glymphatic pathway‐associated arterioles. Slc20a2 deficiency uncovered phosphate homeostasis dysregulation characterized by abnormally high cerebrospinal fluid phosphate levels and hydrocephalus, in addition to basal ganglia calcification. Slc20a2 siRNA knockdown in smooth muscle cells revealed increased susceptibility to high phosphate‐induced calcification. These data suggested that loss of Slc20a2 led to dysregulated phosphate homeostasis and enhanced susceptibility of arteriolar smooth muscle cells to elevated phosphate‐induced calcification. Together, dysregulated cerebrospinal fluid phosphate and enhanced smooth muscle cell susceptibility may predispose to glymphatic pathway‐associated arteriolar calcification.
