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

Neema S. Patel, Jennifer Klett, Katy Pilarzyk, Dong Lee, David A Kass, Frank S. Menniti, Michy P. Kelly

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)217-234
Number of pages18
JournalNeurobiology of Aging
Volume65
DOIs
StatePublished - May 1 2018

Fingerprint

Protein Isoforms
Cyclic GMP
Brain
Hippocampus
Guanosine Monophosphate
Messenger RNA
Cyclic Nucleotides
Nuclear Envelope
Phosphoric Diester Hydrolases
Cerebellum
Dementia
Urinary Bladder
Lung
Membranes

Keywords

  • Aging
  • Aging
  • Allen institute for Brain Science
  • Cerebellum
  • cGMP
  • Development
  • GAPDH
  • Hippocampus
  • Phosphodiesterase
  • Ponceau
  • Prefrontal cortex
  • Striatum

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Identification of new PDE9A isoforms and how their expression and subcellular compartmentalization in the brain change across the life span. / Patel, Neema S.; Klett, Jennifer; Pilarzyk, Katy; Lee, Dong; Kass, David A; Menniti, Frank S.; Kelly, Michy P.

In: Neurobiology of Aging, Vol. 65, 01.05.2018, p. 217-234.

Research output: Contribution to journalArticle

Patel, Neema S. ; Klett, Jennifer ; Pilarzyk, Katy ; Lee, Dong ; Kass, David A ; Menniti, Frank S. ; Kelly, Michy P. / Identification of new PDE9A isoforms and how their expression and subcellular compartmentalization in the brain change across the life span. In: Neurobiology of Aging. 2018 ; Vol. 65. pp. 217-234.
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