Dysfunction of cAMP–Protein Kinase A–Calcium Signaling Axis in Striatal Medium Spiny Neurons: A Role in Schizophrenia and Huntington’s Disease Neuropathology

Fjodorova, Marija; Noakes, Zoe; Fuente, Daniel C. De La; Errington, Adam C.; Li, Meng

doi:10.1016/j.bpsgos.2022.03.010

Cited by 7 publications

(5 citation statements)

References 82 publications

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“…In PD, dysregulated cAMP signalling pathway is associated with levodopa-induced dyskinesia, whereas its dysfunction was also found in HD. [24], [25].…”

Section: Resultsmentioning

confidence: 99%

D^Re^Amocracy: A Method to Capitalize on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing

Savva

Zachariou

Bourdakou

et al. 2023

Preprint

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In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as drugs from clinical trial studies in different phases. To our knowledge, the aggregation of the proposed lists of drugs by previous studies has not been extensively exploited towards the generation of a dynamic reference matrix regarding the disease-related frequencies of drug features such as the modes of action, the initial indications and the targeted pathways. To fill this knowledge gap, we performed a weight-modulated majority voting of the modes of action, initial indications and targeted pathways of the drugs in a well-known repository, namely the Drug Repurposing Hub. Our method, DReAmocracy, exploits this pile of information and creates frequency tables and finally a disease suitability score for each drug. As a testbed, we applied this method to a group of neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's and Multiple Sclerosis). A super-reference table with drug suitability scores has been created for all four neurodegenerative diseases and can be queried for any drug candidate against them. Top-scored drugs for Alzheimer's disease include agomelatine and mirtazapine, for Parkinson's disease apomorphine and pramipexole, for Huntington's fluphezine and perphezine, and for Multiple Sclerosis zonisamide and disopyramide. Overall, DReAmocracy is a methodology that leverages the existing experimental and/or computational knowledge (1) to reveal trends in selected tracks of drug discovery research that includes modes of action, targeted pathways and initial indications for the investigated drugs and (2) to score new candidate drugs for repurposing against a selected disease.

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“…In PD, dysregulated cAMP signalling pathway is associated with levodopa-induced dyskinesia, whereas its dysfunction was also found in HD. [24], [25].…”

Section: Resultsmentioning

confidence: 99%

D^Re^Amocracy: A Method to Capitalize on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing

Savva

Zachariou

Bourdakou

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Moreover, the presence of increased levels of albumin in striatal EVs could be a sign of leakage due to a blood-brain barrier permeability perturbations 72 or to a microglial activation 73 . Interestingly, striatal R6/1 EVs-proteome evoked the alterations in synaptic and signaling pathways that have been described in HD, such as long-term potentiation and depression 74 , cAMP signaling pathway 75 , ErBB/ERK signaling pathways 52 and even pathways of neurodegeneration. These results reinforce the idea that EVs are active contributors to the pathogenesis of the disease 76 , as they are su cient to modulate signaling pathways in the neighboring cells due to their content.…”

Section: Discussionmentioning

confidence: 97%

Motor Skill Learning Modulates Striatal Extracellular Vesicles’ Content in a Mouse Model of Huntington’s Disease

Solana-Balaguer,

Garcia-Segura,

Campoy-Campos

et al. 2024

Preprint

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Huntington’s disease (HD) is a neurological disorder caused by a CAG expansion in the Huntingtin gene (HTT). HD pathology mostly affects striatal medium-sized spiny neurons and results in an altered cortico-striatal function. Recent studies report that motor skill learning, and cortico-striatal stimulation attenuate the neuropathology in HD, resulting in an amelioration of some motor and cognitive functions. During physical training, extracellular vesicles (EVs) are released in many tissues, including the brain, as a potential means for inter-tissue communication. To investigate how motor skill learning, involving acute physical training, modulates EVs crosstalk between cells in the striatum, we trained wild-type (WT) and R6/1 mice, the latter with motor and cognitive deficits, on the accelerating rotarod test, and we isolated their striatal EVs. EVs from R6/1 mice presented alterations in the small exosome population when compared to WT. Proteomic analyses revealed that striatal R6/1 EVs recapitulated signaling and energy deficiencies present in HD. Motor skill learning in R6/1 mice restored the amount of EVs and their protein content in comparison to naïve R6/1 mice. Furthermore, motor skill learning modulated crucial pathways in metabolism and neurodegeneration. All these data provide new insights into the pathogenesis of HD and put striatal EVs in the spotlight to understand the signaling and metabolic alterations in neurodegenerative diseases. Moreover, our results suggest that motor learning is a crucial modulator of cell-to-cell communication in the striatum.

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“…The dysregulation of several kinase-mediated signaling events is implicated in the pathophysiology of schizophrenia [29,49]; however, the functional in PKA in the brain in this disorder are still poorly understood, with few studies examining the activity of this enzyme. Here, we assayed PKA activity in the ACC and DLPFC to determine whether the enzyme activity was significantly altered in subjects with schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, PKA signaling induces transcription factor 4 (TCF4), a protein associated with cognitive deficits in schizophrenia, in cortical neurons [28]. Deficits in PKA signaling are also reported in BCL11B-deficient medium spiny neurons (MSNs) derived from human pluripotent stem cells [29]. BCL11B is a transcription factor and schizophrenia-associated risk gene that regulates PKA signaling in MSNs.…”

Section: Introductionmentioning

confidence: 99%

Activity of Protein Kinase A in the Frontal Cortex in Schizophrenia

Sahay,

Henkel,

Vargas

et al. 2023

Brain Sciences

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Schizophrenia is a serious cognitive disorder characterized by disruptions in neurotransmission, a process requiring the coordination of multiple kinase-mediated signaling events. Evidence suggests that the observed deficits in schizophrenia may be due to imbalances in kinase activity that propagate through an intracellular signaling network. Specifically, 3′-5′-cyclic adenosine monophosphate (cAMP)-associated signaling pathways are coupled to the activation of neurotransmitter receptors and modulate cellular functions through the activation of protein kinase A (PKA), an enzyme whose function is altered in the frontal cortex in schizophrenia. In this study, we measured the activity of PKA in human postmortem anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) tissue from schizophrenia and age- and sex-matched control subjects. No significant differences in PKA activity were observed in male and female individuals in either brain region; however, correlation analyses indicated that PKA activity in the ACC may be influenced by tissue pH in all subjects and by age and tissue pH in females. Our data provide novel insights into the function of PKA in the ACC and DLPFC in schizophrenia.

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Dysfunction of cAMP–Protein Kinase A–Calcium Signaling Axis in Striatal Medium Spiny Neurons: A Role in Schizophrenia and Huntington’s Disease Neuropathology

Cited by 7 publications

References 82 publications

D^Re^Amocracy: A Method to Capitalize on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing

D^Re^Amocracy: A Method to Capitalize on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing

Motor Skill Learning Modulates Striatal Extracellular Vesicles’ Content in a Mouse Model of Huntington’s Disease

Activity of Protein Kinase A in the Frontal Cortex in Schizophrenia

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Dysfunction of cAMP–Protein Kinase A–Calcium Signaling Axis in Striatal Medium Spiny Neurons: A Role in Schizophrenia and Huntington’s Disease Neuropathology

Cited by 7 publications

References 82 publications

DReAmocracy: A Method to Capitalize on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing

DReAmocracy: A Method to Capitalize on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing

Motor Skill Learning Modulates Striatal Extracellular Vesicles’ Content in a Mouse Model of Huntington’s Disease

Activity of Protein Kinase A in the Frontal Cortex in Schizophrenia

Contact Info

Product

Resources

About

D^Re^Amocracy: A Method to Capitalize on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing

D^Re^Amocracy: A Method to Capitalize on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing