PDF(Pubmed)
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.
摘要：
磷酸二酯酶4（PDE4）酶家族的成员调节第二信使环磷酸腺苷（cAMP）的可用性，通过这样做，控制健康和疾病中的细胞过程。特别是,PDE4D与阿尔茨海默病和脆性X综合征中的智力障碍有关。此外，关键PDE4D区域中的单点突变导致2型肢端痉挛（ACRDYS2，也称为灭活PTH/PTHrP信号传导障碍5或iPPSD5），其中智力残疾在90%的患者中与1型（ACRDYS1/iPPSD4）和ACRDYS2特征性的骨骼畸形同时出现。已经提出了两种相反的机制来解释PDE4D中的突变如何导致iPPSD5。第一种机制,“过度激活假设”，表明cAMP/PKA（环磷酸腺苷/蛋白激酶A）信号通过突变PDE4D的过度活性而减少，而第二个,“过度补偿假设”表明突变会降低PDE4D活性。活性的降低被认为会导致细胞cAMP的增加，触发其他PDE亚型的过表达。所产生的过补偿然后降低了细胞cAMP和cAMP/PKA信令的水平。然而,这些提出的机制都没有说明对PDE激活和定位的精细控制，这可能在iPPPSD5的发展中发挥作用。这篇综述将汇集我们对PDE4D在iPPSD5中的作用的理解，并提出对疾病可能机制的新观点。
