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 (“K ATP ”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The K ATP 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.

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Published in Ageing Research Reviews, v. 24, part B, p. 111-125.

Copyright © 2015 Elsevier B.V.

© 2015. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.

The document available for download is the authors' post-peer-review final draft of the article.

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The study was supported by NIH grants P30 AG028383, R01 AG038651, R01 AG042419, R01 HL45742, R01 HL95010, K25 AG043546, and T32 AG 000242.