期刊
BRAIN PATHOLOGY
卷 27, 期 1, 页码 64-76出版社
WILEY-BLACKWELL
DOI: 10.1111/bpa.12362
关键词
cerebral vascular calcification; cerebrospinal fluid; glymphatic spaces; idiopathic basal ganglia calcification; phosphate; Slc20a2
资金
- NIH [HL62329, HL081785, HL114611]
- DOD PRORP [OR120074]
- NHLBI [T32HL007828]
- AHA [13GRNT14360045]
- Laurel Foundation Endowment for Craniofacial Research
- Howard Hughes Medical Institute's Med-into-Grad Program [56006778]
- NIBIB [T32HL007828]
- Fulbright Visiting Scholarship
Idiopathic 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.
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