Identification of new PDE9A isoforms and how their expression and subcellular compartmentalization in the brain change across the life span

NEUROBIOLOGY OF AGING

卷:65

Article

Patel, Neema S.¹  Klett, Jennifer¹  Pilarzyk, Katy¹  Lee, Dong Ik²  Kass, David²  Menniti, Frank S.³  Kelly, Michy P.¹ 

[1] Univ South Carolina, Sch Med, Dept Pharmacol Physiol & Neurosci, 6439 Garners Ferry Rd,VA Bldg 1,3rd Floor,D-12, Columbia, SC 29209 USA

[2] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol,Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

[3] Univ Rhode Isl, George & Anne Ryan Inst Neurosci, Kingston, RI 02881 USA

关键词: Phosphodiesterase;    Hippocampus;    Cerebellum;    Prefrontal cortex;    Striatum;    GAPDH;    Ponceau;    Allen institute for Brain Science;    cGMP;    Aging;    Aging;    Development;   

DOI  :  10.1016/j.neurobiolaging.2018.01.019

来源: Elsevier

【 摘 要 】

3',5'-Cyclic nucleotide phosphodiesterases (PDEs) degrade 3',5' cyclic adenonosine monophosphate (cAMP) and 3',5' cyclic guanosine monophosphate (cGMP), with PDE9A having the highest affinity for cGMP. We show PDE9A6 and 3 novel PDE9 isoforms (PDE9X-100, PDE9X-120, and PDE9X-175) are reliably detected in the brain and lung of mice, whereas PDE9A2 and other isoforms are found elsewhere. PDE9A localizes to the membrane in all organs except the bladder, where it is cytosolic. Brain additionally shows PDE9 in the nuclear fraction. PDE9A mRNA expression/localization dramatically changes across neurodevelopment in a manner that is strikingly consistent between mice and humans (i.e., decreased expression in the hippocampus and cortex and inverted-U in the cerebellum). Study of the 4 PDE9 isoforms in the mouse brain from postnatal day 7 through 24 months similarly identifies dramatic effects of age on expression and subcellular compartmentalization that are isoform specific and brain region specific. Finally, PDE9A mRNA is elevated in the aged human hippocampus with dementia when there is a history of traumatic brain injury. Thus, brain PDE9 is localized to preferentially regulate nuclear- and membrane-proximal pools of cGMP, and its function likely changes across the life span. (C) 2018 Elsevier Inc. All rights reserved.

【 授权许可】

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