Phosphodiesterases in neurodegenerative disorders

Bollen, Eva; Prickaerts, Jos

doi:10.1002/iub.1104

Cited by 106 publications

(79 citation statements)

References 71 publications

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“…For instance, an analysis of the C. neoformans genome (H99 strain) (http://www.broadinstitute.org /annotation/genome/cryptococcus_neoformans/MultiHome .html, November 2013) indicated the existence of at least four candidate phospholipid-translocating ATPases. Considering that the current methods for determination of flippase activity would not discriminate between the activities of these potentially different enzymes, it is possible that C. neoformans could compensate for APT1 deletion by upregulating the expression of other flippase genes, as suggested for other eukaryotic enzymes (55). It is also possible that the contribution of Apt1p to the overall flippase activity of C. neoformans is relatively low and below the sensitivity of the methods used in this study.…”

Section: Discussionmentioning

confidence: 95%

Role of the Apt1 Protein in Polysaccharide Secretion by Cryptococcus neoformans

et al. 2014

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e Flippases are key regulators of membrane asymmetry and secretory mechanisms. Vesicular polysaccharide secretion is essential for the pathogenic mechanisms of Cryptococcus neoformans. On the basis of the observations that flippases are required for polysaccharide secretion in plants and the putative Apt1 flippase is required for cryptococcal virulence, we analyzed the role of this enzyme in polysaccharide release by C. neoformans, using a previously characterized apt1⌬ mutant. Mutant and wild-type (WT) cells shared important phenotypic characteristics, including capsule morphology and dimensions, glucuronoxylomannan (GXM) composition, molecular size, and serological properties. The apt1⌬ mutant, however, produced extracellular vesicles (EVs) with a lower GXM content and different size distribution in comparison with those of WT cells. Our data also suggested a defective intracellular GXM synthesis in mutant cells, in addition to changes in the architecture of the Golgi apparatus. These findings were correlated with diminished GXM production during in vitro growth, macrophage infection, and lung colonization. This phenotype was associated with decreased survival of the mutant in the lungs of infected mice, reduced induction of interleukin-6 (IL-6) cytokine levels, and inefficacy in colonization of the brain. Taken together, our results indicate that the lack of APT1 caused defects in both GXM synthesis and vesicular export to the extracellular milieu by C. neoformans via processes that are apparently related to the pathogenic mechanisms used by this fungus during animal infection.

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Section: Discussionmentioning

confidence: 95%

Role of the Apt1 Protein in Polysaccharide Secretion by Cryptococcus neoformans

et al. 2014

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“…Overview of the specificity of PDE1 to PDE11 for cAMP and/or cGMP. Reproduced with permission from [5].…”

Section: Article Highlightsmentioning

confidence: 99%

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Prickaerts

Heckman

Blokland

2017

Expert Opinion on Investigational Drugs

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144

168

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Introduction: Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer's disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD. PDE inhibitors will also be discussed with respect to adverse effects including safety and tolerability. Expert opinion: The limited available data of clinical studies with PDE inhibitors tested in different populations of AD patients do not allow the drawing of any concrete conclusion yet. Currently, studies with a PDE3 (cilostazol) or PDE9 inhibitor (BI 409,306) are still ongoing in patients with MCI or AD, respectively. Studies with PDE4 inhibitors (HT-0712, roflumilast and BPN14770) in healthy elderly and elderly with age-associated memory impairments indicate that the optimum dose and/or inhibiting the most relevant PDE isoform hold great promise when tested in the appropriate population of patients with MCI or AD eventually. ARTICLE HISTORY

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“…This nucleotide has also been shown to be a neuroprotective agent in different brain disorders, including neurodegenerative diseases such as Huntington, Alzheimer's, and Parkinson's disease (PD) (Bollen and Prickaerts, 2012;MoralesGarcia et al, 2011;Volakakis et al, 2010). Given the important role of cAMP in the brain, specific inhibitors of PDEs are being analyzed as possible therapeutic targets for the treatment of different brain diseases (Garcia-Osta et al, 2012;Menniti et al, 2006;Sharma et al, 2013).…”

Section: Introductionmentioning

confidence: 98%

Silencing phosphodiesterase 7B gene by lentiviral-shRNA interference attenuates neurodegeneration and motor deficits in hemiparkinsonian mice

Morales-García¹,

Aguilar-Morante²,

Hernández-Encinas³

et al. 2015

Neurobiology of Aging

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Different studies have suggested that the nucleotide cyclic adenosine 3', 5'-monophosphate can actively play an important role as a neuroprotective and anti-inflammatory agent after a brain injury. The phosphodiesterase 7 (PDE7) enzyme is one of the enzymes responsible for controlling specifically the intracellular levels of cyclic adenosine 3', 5'-monophosphate in the immune and central nervous systems. Therefore, this enzyme could play an important role in brain inflammation and neurodegeneration. In this regard, using different chemical inhibitors of PDE7 we have demonstrated their neuroprotective and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we have used the toxin 6-hydroxydopamine and lipopolysaccharide to model PD and explore the protective effects of PDE7B deficiency in dopaminergic neurons cell death. Lentivirus-mediated PDE7B deprivation conferred marked in vitro and in vivo neuroprotection against 6-hydroxydopamine and lipopolysaccharide toxicity in dopaminergic neurons and preserved motor function involving the dopamine system in mouse. Our results substantiate previous data and provide a validation of PDE7B enzyme as a valuable new target for therapeutic development in the treatment of PD.

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Phosphodiesterases in neurodegenerative disorders

Cited by 106 publications

References 71 publications

Role of the Apt1 Protein in Polysaccharide Secretion by Cryptococcus neoformans

Role of the Apt1 Protein in Polysaccharide Secretion by Cryptococcus neoformans

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Silencing phosphodiesterase 7B gene by lentiviral-shRNA interference attenuates neurodegeneration and motor deficits in hemiparkinsonian mice

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