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Ageing Res Rev. 2015 Nov;24(Pt B):111-25. doi: 10.1016/j.arr.2015.07.007. Epub 2015 Jul 28.

ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target.

Author information

1
University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA; University of Kentucky, Department of Pathology, Lexington, KY 40536, USA. Electronic address: pnels2@email.uky.edu.
2
University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA; University of Kentucky, Department of Neurology, Lexington, KY, 40536, USA.
3
University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA.
4
Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO 63110, USA.
5
University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY 40536, USA; Department of Biostatistics, Lexington, KY, 40536, USA.

Abstract

The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium ("KATP") channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The KATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9/SUR2 may provide a "druggable target", relevant perhaps to both HS-Aging and Alzheimer's disease. We conclude that more work is required to better understand the roles of ABCC9/SUR2 in the human brain during health and disease conditions.

KEYWORDS:

ABCC8; Arteriolosclerosis; GWAS; Hippocampus; Neuropathology; Oldest-old; SUR1; SUR2A; SUR2Ab; SUR2B

PMID:
26226329
PMCID:
PMC4661124
DOI:
10.1016/j.arr.2015.07.007
[Indexed for MEDLINE]
Free PMC Article

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