Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington′s disease transgenic mice prior to the onset of motor symptoms

Hebb, Andrea L.O.; Robertson, Harold A.; Denovan‐Wright, Eileen M.

doi:10.1016/j.neuroscience.2003.11.009

Cited by 152 publications

(130 citation statements)

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“…41 In addition, decreased PDE10 mRNA and protein levels have been described in the striatum of patients of Huntington's disease. 42 Based on its localization in the hippocampus and the increases in PDE10A after LTP induction, 43 a role for this protein in memory and cognition has also been proposed. This PDE may represent an important target to treat cognitive deficits associated to schizophrenia.…”

mentioning

confidence: 99%

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

García‐Osta¹,

Cuadrado‐Tejedor²,

García‐Barroso³

et al. 2012

ACS Chem. Neurosci.

219

179

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Alzheimer's disease (AD) is the most common form of dementia among the elderly. In AD patients, memory loss is accompanied by the formation of beta-amyloid plaques and the appearance of tau in a pathological form. Given the lack of effective treatments for AD, the development of new management strategies for these patients is critical. The continued failure to find effective therapies using molecules aimed at addressing the anti-beta amyloid pathology has led researchers to focus on other non-amyloid-based approaches to restore memory function. Promising non-amyloid related candidate targets include phosphosdiesterases (PDEs), and indeed, Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD. More recently, PDE5 inhibitors have also been shown to effectively restore memory function. Accordingly, inhibitors of other members of the PDE family may also improve memory performance in AD and non-AD animal models. Hence, in this review, we will summarize the data supporting the use of PDE inhibitors as cognitive enhancers and we will discuss the possible mechanisms of action underlying these effects. We shall also adopt a medicinal chemistry perspective that leads us to propose the most promising PDE candidates on the basis of inhibitor selectivity, brain distribution, and mechanism of action.

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mentioning

confidence: 99%

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

García‐Osta¹,

Cuadrado‐Tejedor²,

García‐Barroso³

et al. 2012

ACS Chem. Neurosci.

219

179

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“…PDE10 is highly expressed in brain striatum (13)(14)(15)(16). Reduction of PDE10A mRNA and protein levels in striatum of transgenic mice implies a role of PDE10A in Huntington's disease (17,18). Knockout mice experiments suggest that PDE10A is involved in regulating striatal output, possibly by reducing the sensitivity of medium spiny neurons to glutamatergic excitation (19).…”

mentioning

confidence: 99%

Structural insight into substrate specificity of phosphodiesterase 10

Wang

Liu

Hou

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

103

139

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Phosphodiesterases (PDEs) hydrolyze the second messengers cAMP and cGMP. It remains unknown how individual PDE families selectively recognize cAMP and cGMP. This work reports structural studies on substrate specificity. The crystal structures of the catalytic domains of the D674A and D564N mutants of PDE10A2 in complex with cAMP and cGMP reveal that two substrates bind to the active site with the same syn configuration but different orientations and interactions. The products AMP and GMP bind PDE10A2 with the anti configuration and interact with both divalent metals, in contrast to no direct contact of the substrates. The structures suggest that the syn configurations of cAMP and cGMP are the genuine substrates for PDE10 and the specificity is achieved through the different interactions and conformations of the substrates. The PDE10A2 structures also show that the conformation of the invariant glutamine is locked by two hydrogen bonds and is unlikely to switch for substrate recognition. Sequence alignment shows a potential pocket, in which variation of amino acids across PDE families defines the size and shape of the pocket and thus determines the substrate specificity.crystal structure ͉ cyclic nucleotides cAMP and cGMP C yclic nucleotide phosphodiesterases (PDEs) are enzymes hydrolyzing the second messengers adenosine and guanosine 3Ј,5Ј-cyclic monophosphates (cAMP and cGMP). The human genome encodes 21 PDE genes that are categorized into 11 families (1, 2). Selective inhibitors against individual PDE families have been developed as therapeutics for treatment of various human diseases (3-8). The best known examples are the PDE5 inhibitors sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) that have been used for treatment of male erectile dysfunction (5). Sildenafil (Revatio) has also been approved for treatment of pulmonary hypertension (9). PDE10 was independently identified by three groups in 1999 and shows a dual activity on hydrolysis of both cAMP and cGMP (10-12). PDE10 is highly expressed in brain striatum (13-16). Reduction of PDE10A mRNA and protein levels in striatum of transgenic mice implies a role of PDE10A in Huntington's disease (17,18). Knockout mice experiments suggest that PDE10A is involved in regulating striatal output, possibly by reducing the sensitivity of medium spiny neurons to glutamatergic excitation (19). The PDE10 inhibitor papaverine is effective in improving executive function deficits associated with schizophrenia, and therefore inhibition of PDE10 may represent an approach to treatment of psychosis (20,21).PDE families contain a variable N-terminal regulatory domain and a conserved C-terminal catalytic domain. Individual PDE families show different substrate preferences. Crystal structures have been reported for the catalytic domains of seven PDE families in the unliganded form or in complex with inhibitors or products: PDE1B, PDE2A, PDE3B, PDE4B/4D, PDE5A, PDE7A, and PDE9A (22-34). However, it remains a puzzle how the conserved catalytic pocket of the PDE famili...

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“…The gene codes for the protein huntingtin (htt) and the mutant variant thus has an extended number of glutamine repeats, varying from 11 to 34 in normal individuals and 36 to 121 units in HD patients (The Huntington's Disease Collaborative Research Group, 1993). The role of huntingtin is yet unclear, but evidence suggests that it is involved in neurodevelopmental processes (e.g., Hebb, et al, 2004). The pathophysiological mechanisms of Huntington's Disease are poorly understood, but research with transgenic animal models of the disorder is providing insights into the causative factors and potential treatments.…”

Section: Neuropathology Of Huntington's Diseasementioning

confidence: 99%

“…In particular, there is evidence showing that the mutant huntingtin interferes selectively with transcription factors in the medium spiny neurons (Gomez, et al, 2006). In transgenic mice, Hebb et al (2004) observed decreased levels of PDE10A mRNA before motor symptoms appear and Gomez et al (2006) observed decreased levels of DARPP-32 mRNA in MSNs, but not in other DARPP-32 mRNA expressing tissue, such as the kidneys.…”

Section: The Mutant Huntingtin Protein Destabilizes Cellsmentioning

confidence: 99%

Computational Investigations of Cognitive Impairment in Huntington's Disease

Davelaar¹

2012

Huntington's Disease - Core Concepts and Current Advances

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Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington′s disease transgenic mice prior to the onset of motor symptoms

Cited by 152 publications

References 75 publications

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

Structural insight into substrate specificity of phosphodiesterase 10

Computational Investigations of Cognitive Impairment in Huntington's Disease

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