Allosteric modulation of protein kinase A in individuals affected by NLPD‐PKA, a neurodegenerative disease in which the PRKAR1B L50R variant is expressed

FEBS Journal, Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

Protein kinase A (PKA) is a crucial signaling enzyme in neurons, with its dysregulation being implicated neurodegenerative diseases. Assembly of the PKA holoenzyme, comprising dimer heterodimers regulatory (R) and catalytic (C) subunits, ensures allosteric regulation functional specificity. Recently, we defined RIβ-L50R variant as causative mutation that triggers protein aggregation rare disease, neuronal loss, parkinsonism driven by (NLPD-PKA). However, mechanism underlying uncontrolled connection to outcomes leading clinical symptoms remains elusive. In this study, established an vitro model using patient-derived cells for personalized approach employed direct measurements purified proteins investigate disease mechanisms controlled environment. Structural analysis circular dichroism spectroscopy revealed cellular resulted from misfolded RIβ-subunits, preventing holoenzyme assembly anchoring through A-kinase (AKAPs). While maintaining high affinity C-subunit, resulting RIβ-L50R:C heterodimer exhibits reduced cooperativity, requiring lower cAMP concentrations dissociation. Consequently, there was increased translocation C-subunit into nucleus, impacting gene expression. We successfully introducing decreased RIβ:C dissociation response elevated levels. This research thus sets stage developing therapeutic strategies modulate allostery, exerting control over unique molecular signatures identified disease-associated transcriptome profile.

Language: Английский

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A high-performance fluorescent sensor spatiotemporally reveals cell-type specific regulation of intracellular adenosine in vivo

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 7, 2025

Language: Английский

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Key differences in regulation of opioid receptors localized to presynaptic terminals compared to somas: Relevance for novel therapeutics

Neuropharmacology, Journal Year: 2022, Volume and Issue: 226, P. 109408 - 109408

Published: Dec. 28, 2022

Opioid receptors are G protein-coupled (GPCRs) that regulate activity within peripheral, subcortical and cortical circuits involved in pain, reward, aversion processing. expressed both presynaptic terminals where they inhibit neurotransmitter release postsynaptic locations act to hyperpolarize neurons reduce activity. Agonist activation of at the plasma membrane signal via ion channels or cytoplasmic second messengers. binding initiates regulatory processes include phosphorylation by protein receptor kinases (GRKs) recruitment beta-arrestins desensitize internalize receptors. also couple effectors from endosomes activating intracellular enzymes kinases. In contrast opioid receptors, localized resistant desensitization such there is no loss signaling continuous presence opioids over same time scale. Thus, balance expressing pre- shifted toward inhibition during exposure. The functional implication this shift not often acknowledged behavioral studies. This review covers what currently understood about regulation opioid/nociceptin with an emphasis on pain reward circuits. Importantly, critical gaps understanding area, as well opportunities further understand brain article part Special Issue "Opioid-induced changes addiction circuits".

Language: Английский

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From Diagnosis to Treatment: A Comprehensive Review of Biomarkers and Therapeutic Advances in Parkinson’s Disease

Annals of Neurosciences, Journal Year: 2023, Volume and Issue: 32(1), P. 51 - 57

Published: Nov. 1, 2023

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons, resulting in motor symptoms. Ongoing research shows promise for long-term solutions. Studies highlight dysregulation Syt11 and α-synuclein (α-syn) PD. Disrupted α-syn homeostasis due to palmitoylation contributes its aggregation, potentially playing role PD pathology. aggregates stool samples show as an early diagnostic biomarker. Vocal impairments may be linked α-syn-induced neuropathology. Irisin, produced after exercise, promotes degradation pathologic α-syn. Progress has been made identifying biomarkers. Retinal thinning abnormal protein skin biopsies provide noninvasive indicators. Blood-based biomarkers like α-syn, DJ-1, LRRK2 hold but face limitations. Artificial intelligence (AI) models enhance mitophagy, detect through sleep-breathing signals, improve survival. AI analysis aids assessment risk prediction. Further understanding involves studying pathological seeds genetic mutations. Adenosine receptor regulation relates early-onset PD, specific gene mutations impact patient Differentiated-induced pluripotent stem cells offer potential cell replacement therapy. Autoimmune features T-cell involvement suggest intervention targets. Stem cell-based therapies neurostimulation strategies improving function. Imaging reveals increased central inflammation suggesting inflammatory role. Machine learning algorithms home gait speed monitoring aid diagnosis progression tracking. Abnormal putamen gradients reflect dysfunction. Antiepileptic drug prescriptions are associated with risk. Personalized medicine, gut-brain axis involvement, vestibular stimulation therapy treatment avenues. Genetic engineering techniques deep brain alleviating technological advancements screening, diagnosis, treatment, bringing hope affected individuals.

Language: Английский

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Modulation of D3R Splicing, Signaling, and Expression by D1R through PKA→PTB Phosphorylation

Biomedicines, Journal Year: 2024, Volume and Issue: 12(1), P. 206 - 206

Published: Jan. 17, 2024

The D1R and D3R receptors functionally synergistically interact in striatonigral neurons. Dopaminergic denervation turns this interaction antagonistic, which is correlated with a decrement D3nf isoform an increment membranal expression. mechanisms of such changes are attributed to the dysregulation expression their isoforms. cause mechanism phenomenon remain unknown. produces PKA activity; we propose that lack phosphorylation PTB (regulator alternative splicing) by splicing functionality. By using silico analysis, found mRNA has motifs for binding and, RIP, co-precipitates PTB. Moreover, activation via promotes phosphorylation. Acute 5-day blockade decreases mRNA. treatment reduces D3R, D3nf, protein cytoplasm increases membrane nucleus. Finally, mimics effect dopaminergic signaling. Thus, our data indicate through PKA→PTB, modulates splicing, expression, signaling, altered during or stimulation denervation.

Language: Английский

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