Gardner, Oliver FW;
Bai, Tianshu;
Baillie, George S;
Ferretti, Patrizia;
(2024)
Phosphodiesterase 4D activity in acrodysostosis-associated neural pathology: too much or too little?
Brain Communications
, 6
(4)
, Article fcae225. 10.1093/braincomms/fcae225.
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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 ∼90% of patients alongside the skeletal dysmorphologies that 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 overexpression 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 localization, 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.
| Type: | Article |
|---|---|
| Title: | Phosphodiesterase 4D activity in acrodysostosis-associated neural pathology: too much or too little? |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/braincomms/fcae225 |
| Publisher version: | http://dx.doi.org/10.1093/braincomms/fcae225 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences, Neurosciences & Neurology, acrodysostosis, PDE4D, cAMP, protein kinase A, CAMP-SPECIFIC PHOSPHODIESTERASE, IDENTIFIES PDE4D MUTATIONS, DEPENDENT PROTEIN-KINASE, VERBAL WORD MEMORY, PRKAR1A MUTATION, CATALYTIC UNIT, GENE, PHOSPHORYLATION, ROFLUMILAST, ACTIVATION |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10195107 |
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