Gardner, O. F.W., Bai, T., Baillie, G. S. and Ferretti, P. (2024) Phosphodiesterase 4D activity in acrodysostosis-associated neural pathology: too much or too little? Brain Communications, (doi: 10.1093/braincomms/fcae225) (Early Online Publication)
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Abstract
Members of the phosphodiesterase 4 (PDE4) enzyme family regulate the availability of the secondary messenger cyclic adenosine monophosphate (cAMP) and by doing so control cellular processes in health and disease. In particular, PDE4D has been associated with Alzheimer’s disease and the intellectual disability seen in fragile X syndrome. Furthermore, single point mutations in critical PDE4D regions cause acrodysostosis type 2/(ACRDYS2, also referred to as inactivating PTH/PTHrP signalling disorder 5 or iPPSD5), where intellectual disability is seen in approximately 90% of patients alongside the skeletal dysmorphologies which are characteristic of acrodysostosis type 1 (ACRDYS1/iPPSD4) and ACRDYS2. Two contrasting mechanisms have been proposed to explain how mutations in PDE4D cause iPPSD5. The first mechanism, the over-activation hypothesis, suggests that cAMP/PKA (cyclic adenosine monophosphate/protein kinase A) signalling is reduced by the overactivity of mutant PDE4D, whilst the second, the over-compensation hypothesis suggests that mutations reduce PDE4D activity. That reduction in activity is proposed to cause an increase in cellular cAMP, triggering the over-expression of other PDE isoforms. The resulting over-compensation then reduces cellular cAMP and the levels of cAMP/PKA signalling. However, neither of these proposed mechanisms accounts for the fine control of PDE activation and localisation, which are likely to play a role in the development of iPPSD5. This review will draw together our understanding of the role of PDE4D in iPPSD5 and present a novel perspective on possible mechanisms of disease.
Item Type: | Articles |
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Additional Information: | This work was supported by Great Ormond Street Hospital Charity (GOSHC), National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre (NIHR GOSH BRC) and the Medical Research Council (MR/Y003640/1). |
Status: | Early Online Publication |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Baillie, Professor George |
Authors: | Gardner, O. F.W., Bai, T., Baillie, G. S., and Ferretti, P. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
Journal Name: | Brain Communications |
Publisher: | Oxford University Press |
ISSN: | 2632-1297 |
ISSN (Online): | 2632-1297 |
Published Online: | 29 June 2024 |
Copyright Holders: | Copyright © The Author(s) 2024 |
First Published: | First published in Brain Communications 2024 |
Publisher Policy: | Reproduced under a Creative Commons licence |
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