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Background: GNAO1-related disorders (GNAO1-RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the GNAO1 gene. Dyskinetic crises, marked by sudden and intense exacerbations of abnormal involuntary movements, present a significant challenge in GNAO1-RD. Objectives: This study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies. Methods: A Delphi consensus process was conducted involving international experts in GNAO1-RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise. Results: Consensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis. Conclusion: This consensus provides a foundation for understanding and managing dyskinetic crises in GNAO1-RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future GNAO1-RD research.
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Introduction: Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) poses a major clinical challenge to ICI therapy for cancer, with 13% of cases halting ICI therapy and ICI-IA being difficult to identify for timely referral to a rheumatologist. The objective of this study was to rapidly identify ICI-IA patients in clinical data and assess associated immune-related adverse events (irAEs) and risk factors. Methods: We conducted a retrospective study of the electronic health records (EHRs) of 89 patients who developed ICI-IA out of 2451 cancer patients who received ICI therapy at Northwestern University between March 2011 to January 2021. Logistic regression and random forest machine learning models were trained on all EHR diagnoses, labs, medications, and procedures to identify ICI-IA patients and EHR codes indicating ICI-IA. Multivariate logistic regression was then used to test associations between ICI-IA and cancer type, ICI regimen, and comorbid irAEs. Results: Logistic regression and random forest models identified ICI-IA patients with accuracies of 0.79 and 0.80, respectively. Key EHR features from the random forest model included ICI-IA relevant features (joint pain, steroid prescription, rheumatoid factor tests) and features suggesting comorbid irAEs (thyroid function tests, pruritus, triamcinolone prescription). Compared to 871 adjudicated ICI patients who did not develop arthritis, ICI-IA patients had higher odds of developing cutaneous (odds ratio [OR]=2.66; 95% Confidence Interval [CI] 1.63-4.35), endocrine (OR=2.09; 95% CI 1.15-3.80), or gastrointestinal (OR=2.88; 95% CI 1.76-4.72) irAEs adjusting for demographics, cancer type, and ICI regimen. Melanoma (OR=1.99; 95% CI 1.08-3.65) and renal cell carcinoma (OR=2.03; 95% CI 1.06-3.84) patients were more likely to develop ICI-IA compared to lung cancer patients. Patients on nivolumab+ipilimumab were more likely to develop ICI-IA compared to patients on pembrolizumab (OR=1.86; 95% CI 1.01-3.43). Discussion: Our machine learning models rapidly identified patients with ICI-IA in EHR data and elucidated clinical features indicative of comorbid irAEs. Patients with ICI-IA were significantly more likely to also develop cutaneous, endocrine, and gastrointestinal irAEs during their clinical course compared to ICI therapy patients without ICI-IA.
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Antineoplásicos Inmunológicos , Artritis , Neoplasias Renales , Melanoma , Humanos , Antineoplásicos Inmunológicos/uso terapéutico , Estudios Retrospectivos , Artritis/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológicoRESUMEN
Dystonia, typically characterized by slow repetitive involuntary movements, stiff abnormal postures, and hypertonia, is common among individuals with cerebral palsy (CP). Dystonia can interfere with activities and have considerable impact on motor function, pain/comfort, and ease of caregiving. Although pharmacological and neurosurgical approaches are used clinically in individuals with CP and dystonia that is causing interference, evidence to support these options is limited. This clinical practice guideline update comprises 10 evidence-based recommendations on the use of pharmacological and neurosurgical interventions for individuals with CP and dystonia causing interference, developed by an international expert panel following the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. The recommendations are intended to help inform clinicians in their use of these management options for individuals with CP and dystonia, and to guide a shared decision-making process in selecting a management approach that is aligned with the individual's and the family's values and preferences.
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Parálisis Cerebral , Distonía , Parálisis Cerebral/cirugía , Parálisis Cerebral/complicaciones , Humanos , Distonía/tratamiento farmacológico , Distonía/cirugía , Procedimientos Neuroquirúrgicos/normas , Guías de Práctica Clínica como Asunto/normasRESUMEN
Sensory processing and sensorimotor integration are abnormal in dystonia, including impaired modulation of beta-corticomuscular coherence. However, cortex-muscle interactions in either direction are rarely described, with reports limited predominantly to investigation of linear coupling, using corticomuscular coherence or Granger causality. Information-theoretic tools such as transfer entropy detect both linear and non-linear interactions between processes. This observational case-control study applies transfer entropy to determine intra- and cross-frequency cortex-muscle coupling in young people with dystonia/dystonic cerebral palsy. Fifteen children with dystonia/dystonic cerebral palsy and 13 controls, aged 12-18 years, performed a grasp task with their dominant hand. Mechanical perturbations were provided by an electromechanical tapper. Bipolar scalp EEG over contralateral sensorimotor cortex and surface EMG over first dorsal interosseous were recorded. Multi-scale wavelet transfer entropy was applied to decompose signals into functional frequency bands of oscillatory activity and to quantify intra- and cross-frequency coupling between brain and muscle. Statistical significance against the null hypothesis of zero transfer entropy was established, setting individual 95% confidence thresholds. The proportion of individuals in each group showing significant transfer entropy for each frequency combination/direction was compared using Fisher's exact test, correcting for multiple comparisons. Intra-frequency transfer entropy was detected in all participants bidirectionally in the beta (16-32â Hz) range and in most participants from EEG to EMG in the alpha (8-16â Hz) range. Cross-frequency transfer entropy across multiple frequency bands was largely similar between groups, but a specific coupling from low-frequency EMG to beta EEG was significantly reduced in dystonia [P = 0.0061 (corrected)]. The demonstration of bidirectional cortex-muscle communication in dystonia emphasizes the value of transfer entropy for exploring neural communications in neurological disorders. The novel finding of diminished coupling from low-frequency EMG to beta EEG in dystonia suggests impaired cortical feedback of proprioceptive information with a specific frequency signature that could be relevant to the origin of the excessive low-frequency drive to muscle.
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In adult white adipose tissue, cold or ß3-adrenoceptor activation promotes the appearance of thermogenic beige adipocytes. Our comprehensive single-cell analysis revealed that these cells arise through the reprogramming of existing adipogenic trajectories, rather than from a single precursor. These trajectories predominantly arise from SM22-expressing vascular mural progenitor cells. Central in this transition is the activation of Adrb3 in mature adipocytes, leading to subsequent upregulation of Adrb1 in primed progenitors. Under thermoneutral conditions, synergistic activation of both Adrb3 and Adrb1 recapitulates the pattern of cold-induced SM22+ cell recruitment. Lipolysis-derived eicosanoids, specifically docosahexaenoic acid (DHA) and arachidonic acid (AA) prime these processes and in vitro, were sufficient to recapitulate progenitor cells priming. Collectively, our findings provide a robust model for cold-induced beige adipogenesis, emphasizing a profound relationship between mature adipocytes and mural cells during cold acclimation, and revealing the metabolic potential of this unique cellular reservoir.
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Mitochondrial dysfunction has been attributed to many disease indications, including metabolic, cardiovascular, neoplastic, and neurodegenerative diseases. Dynamin related protein 1 (DRP1) is crucial in regulating mitochondrial fission and maintaining mitochondrial homeostasis. MiD49 is a dynamic peripheral protein receptor on the surface of the mitochondrial membrane that recruits DRP1 protein to induce mitochondrial binary fission. By targeting the protein-protein interaction of DRP1/MiD49, we have discovered a novel and potent allosteric DRP1 inhibitor that inhibits mitochondria fragmentation in vitro. X-ray cocrystal structure revealed that it locked the closed DRP1 conformation by induced dimerization.
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Dystonia is now widely accepted as a network disorder, with multiple brain regions and their interconnections playing a potential role in the pathophysiology. This model reconciles what could previously have been viewed as conflicting findings regarding the neuroanatomical and neurophysiological characteristics of the disorder, but there are still significant gaps in scientific understanding of the underlying pathophysiology. One of the greatest unmet challenges is to understand the network model of dystonia in the context of the developing brain. This article outlines how research in childhood dystonia supports and contributes to the network theory and highlights aspects where data from paediatric studies has revealed novel and unique physiological insights, with important implications for understanding dystonia across the lifespan.
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Distonía , Trastornos Distónicos , Humanos , Niño , Encéfalo , InvestigaciónRESUMEN
Background: The International Parkinson and Movement Disorders Society (MDS) set up a working group on pediatric movement disorders (MDS Task Force on Pediatrics) to generate recommendations to guide the transition process from pediatrics to adult health care systems in patients with childhood-onset movement disorders. Methods: To develop recommendations for transitional care for childhood onset movement disorders, we used a formal consensus development process, using a multi-round, web-based Delphi survey. The Delphi survey was based on the results of the scoping review of the literature and the results of a survey of MDS members on transition practices. Through iterative discussions, we generated the recommendations included in the survey. The MDS Task Force on Pediatrics were the voting members for the Delphi survey. The task force members comprise 23 child and adult neurologists with expertise in the field of movement disorders and from all regions of the world. Results: Fifteen recommendations divided across four different areas were made pertaining to: (1) team composition and structure, (2) planning and readiness, (3) goals of care, and (4) administration and research. All recommendations achieved consensus with a median score of 7 or greater. Conclusion: Recommendations on providing transitional care for patients with childhood onset movement disorders are provided. Nevertheless several challenges remain in the implementation of these recommendations, related to health infrastructure and the distribution of health resources, and the availability of knowledgeable and interested practitioners. Research on the influence of transitional care programs on outcomes in childhood onset movement disorders is much needed.
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In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose 'fetal acetylcholine receptor antibody-related disorders' (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.
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Artrogriposis , Miastenia Gravis , Enfermedades Neuromusculares , Embarazo , Femenino , Adulto , Humanos , Inmunoglobulinas Intravenosas , Receptores Colinérgicos , Miastenia Gravis/terapia , Miastenia Gravis/complicaciones , Autoanticuerpos , Artrogriposis/complicacionesRESUMEN
The "epilepsy-dyskinesia" spectrum is increasingly recognized in neurogenetic and neurometabolic conditions. It can be challenging to diagnose because of clinical and genetic heterogeneity, atypical or nonspecific presentations, and the rarity of each diagnostic entity. This is further complicated by the lack of sensitive or specific biomarkers for most nonenzymatic neurometabolic conditions. Nevertheless, clinical awareness and timely diagnosis are paramount to facilitate appropriate prognostication, counseling, and management.This report describes a case of a teenage girl who had presented at 14 months with a protracted illness manifesting as gastrointestinal upset and associated motor and cognitive regression. A choreoathetoid movement disorder, truncal ataxia, and microcephaly evolved after the acute phase. Neurometabolic and inflammatory investigations, EEG, brain MRI, muscle biopsy (including respiratory chain enzyme studies), and targeted genetic testing were unremarkable. A second distinct regression phase ensued at 14 years consisting of encephalopathy, multifocal motor seizures, absent deep tendon reflexes and worsening movements, gut dysmotility, and dysphagia. Video EEGs showed an evolving developmental and epileptic encephalopathy with multifocal seizures and nonepileptic movements. MRI of the brain revealed evolving and fluctuating patchy bihemispheric cortical changes, cerebellar atrophy with signal change, mild generalized brain volume loss, and abnormal lactate on MR spectroscopy. The article discusses the differential diagnostic approach and management options for patients presenting with neurologic regression, encephalopathy, seizures, and hyperkinetic movements. It also emphasizes the utility of next-generation sequencing in providing a rapid, efficient, cost-effective way of determining the underlying etiology of complex neurologic presentations.
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Encefalopatías , Epilepsia , Femenino , Adolescente , Humanos , Hipercinesia/diagnóstico , Encefalopatías/complicaciones , Convulsiones/complicaciones , Epilepsia/diagnóstico , Razonamiento Clínico , Electroencefalografía/métodosRESUMEN
There is a lack of imaging markers revealing the functional characteristics of different brain regions in paediatric dystonia. In this observational study, we assessed the utility of [18F]2-fluoro-2-deoxy-D-glucose (FDG)-PET in understanding dystonia pathophysiology by revealing specific resting awake brain glucose metabolism patterns in different childhood dystonia subgroups. PET scans from 267 children with dystonia being evaluated for possible deep brain stimulation surgery between September 2007 and February 2018 at Evelina London Children's Hospital (ELCH), UK, were examined. Scans without gross anatomical abnormality (e.g. large cysts, significant ventriculomegaly; n = 240) were analysed with Statistical Parametric Mapping (SPM12). Glucose metabolism patterns were examined in the 144/240 (60%) cases with the 10 commonest childhood-onset dystonias, focusing on nine anatomical regions. A group of 39 adult controls was used for comparisons. The genetic dystonias were associated with the following genes: TOR1A, THAP1, SGCE, KMT2B, HPRT1 (Lesch Nyhan disease), PANK2 and GCDH (Glutaric Aciduria type 1). The acquired cerebral palsy (CP) cases were divided into those related to prematurity (CP-Preterm), neonatal jaundice/kernicterus (CP-Kernicterus) and hypoxic-ischaemic encephalopathy (CP-Term). Each dystonia subgroup had distinct patterns of altered FDG-PET uptake. Focal glucose hypometabolism of the pallidi, putamina or both, was the commonest finding, except in PANK2, where basal ganglia metabolism appeared normal. HPRT1 uniquely showed glucose hypometabolism across all nine cerebral regions. Temporal lobe glucose hypometabolism was found in KMT2B, HPRT1 and CP-Kernicterus. Frontal lobe hypometabolism was found in SGCE, HPRT1 and PANK2. Thalamic and brainstem hypometabolism were seen only in HPRT1, CP-Preterm and CP-term dystonia cases. The combination of frontal and parietal lobe hypermetabolism was uniquely found in CP-term cases. PANK2 cases showed a distinct combination of parietal hypermetabolism with cerebellar hypometabolism but intact putaminal-pallidal glucose metabolism. HPRT1, PANK2, CP-kernicterus and CP-preterm cases had cerebellar and insula glucose hypometabolism as well as parietal glucose hypermetabolism. The study findings offer insights into the pathophysiology of dystonia and support the network theory for dystonia pathogenesis. 'Signature' patterns for each dystonia subgroup could be a useful biomarker to guide differential diagnosis and inform personalized management strategies.
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Parálisis Cerebral , Distonía , Trastornos Distónicos , Kernicterus , Adulto , Recién Nacido , Humanos , Niño , Fluorodesoxiglucosa F18/metabolismo , Distonía/metabolismo , Kernicterus/complicaciones , Kernicterus/metabolismo , Encéfalo/metabolismo , Trastornos Distónicos/metabolismo , Tomografía de Emisión de Positrones/métodos , Glucosa/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismoRESUMEN
OBJECTIVES: In adults with dystonia Probabilistic Stimulation Mapping (PSM) has identified putative "sweet spots" for stimulation. We aimed to apply PSM to a cohort of Children and Young People (CYP) following DBS surgery. METHODS: Pre-operative MRI and post-operative CT images were co-registered for 52 CYP undergoing bilateral pallidal DBS (n = 31 genetic/idiopathic dystonia, and n = 21 Cerebral Palsy (CP)). DBS electrodes (n = 104) were automatically detected, and Volumes of Tissue Activation (VTA) derived from individual patient stimulation settings. VTAs were normalised to the MNI105 space, weighted by percentage improvement in Burke-Fahn-Marsden Dystonia Rating scale (BFMDRS) at one-year post surgery and mean improvement was calculated for each voxel. RESULTS: For the genetic/idiopathic dystonia group, BFMDRS improvement was associated with stimulation across a broad volume of the GPi. A spatial clustering of the upper 25th percentile of voxels corresponded with a more delineated volume within the posterior ventrolateral GPi. The MNI coordinates of the centroid of this volume (X = -23.0, Y = -10.5 and Z = -3.5) were posterior and superior to the typical target for electrode placement. Volume of VTA overlap with a previously published "sweet spots" correlated with improvement following surgery. In contrast, there was minimal BFMDRS improvement for the CP group, no spatial clustering of efficacious clusters and a correlation between established "sweet spots" could not be established. CONCLUSIONS: PSM in CYP with genetic/idiopathic dystonia suggests the presence of a "sweet spot" for electrode placement within the GPi, consistent with previous studies. Further work is required to identify and validate putative "sweet spots" across different cohorts of patients.
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Parálisis Cerebral , Estimulación Encefálica Profunda , Distonía , Trastornos Distónicos , Adulto , Niño , Humanos , Adolescente , Distonía/diagnóstico por imagen , Distonía/terapia , Trastornos Distónicos/diagnóstico por imagen , Trastornos Distónicos/terapia , Globo Pálido/diagnóstico por imagenRESUMEN
Background: There is currently very limited data related to transition services for movement disorders. Objectives: Movement Disorders Society (MDS) Task Force on Pediatrics conducted a survey of current provision of transition for young adults with movement disorders. Methods: The survey questionnaire was based on review of available evidence, with questions designed to capture service location, transition clinic structure, and core issues discussed. The questionnaire was digitalized as an online survey and sent to all members of the MDS. Results: Responses were received from a total of 252 MDS members representing 67 countries. Of the responders, 59% confirmed that they provided transition clinics for adolescents with movement disorders. Overall, there was some consensus regarding transition services in terms of patient age at transition, movement disorder etiologies, staffing the service, and medical/social issues discussed. Conclusion: This survey provides first-hand data of existing movement disorder transition services and provides useful insights on transition clinics.
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BACKGROUND: There is a significant gap in knowledge about rehabilitation techniques and strategies that can help children and young people with hyperkinetic movement disorders (HMD) including dystonia to successfully perform daily activities and improve overall participation. A promising approach to support skill acquisition is the Cognitive Orientation to daily Occupational Performance (CO-OP) intervention. CO-OP uses cognitive strategies to help patients generate their own solutions to overcome self-identified problems encountered in everyday living. PURPOSE: 1. To identify and categorize strategies used by children with HMD to support skill acquisition during CO-OP; 2. To review the possible underlying mechanisms that might contribute to the cognitive strategies, in order to facilitate further studies for developing focused rehabilitation approaches. METHODS: A secondary analysis was performed on video-recorded data from a previous study exploring the efficacy of CO-OP for childhood onset HMD, in which CO-OP therapy sessions were delivered by a single occupational therapist. For the purpose of this study, we reviewed a total of 40 randomly selected hours of video footage of CO-OP sessions delivered to six participants (age 6-19 years) over ten intervention sessions. An observational recording sheet was applied to identify systematically the participants' or therapist's verbalizations of cognitive strategies during the therapy. The strategies were classified into six categories in line with published literature. RESULTS: Strategies used by HMD participants included distraction, externally focussed attention, internally focussed attention, emotion self-regulation, motor imagery and mental self-guidance. We postulate different underlying working mechanisms for these strategies, which have implications for the therapeutic management of children and young people with HMD including dystonia. CONCLUSIONS: Cognitive strategy training can fundamentally change and improve motor performance. On-going work will address both the underlying neural mechanisms of therapeutic change and the mediators and moderators that influence how change unfolds.
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Distonía , Trastornos Distónicos , Terapia Ocupacional , Niño , Humanos , Adolescente , Adulto Joven , Adulto , Distonía/terapia , Terapia Ocupacional/métodos , Trastornos Distónicos/terapia , CogniciónRESUMEN
BACKGROUND: Most reported patients carrying GNAO1 mutations showed a severe phenotype characterized by early-onset epileptic encephalopathy and/or chorea. OBJECTIVE: The aim was to characterize the clinical and genetic features of patients with mild GNAO1-related phenotype with prominent movement disorders. METHODS: We included patients diagnosed with GNAO1-related movement disorders of delayed onset (>2 years). Patients experiencing either severe or profound intellectual disability or early-onset epileptic encephalopathy were excluded. RESULTS: Twenty-four patients and 1 asymptomatic subject were included. All patients showed dystonia as prominent movement disorder. Dystonia was focal in 1, segmental in 6, multifocal in 4, and generalized in 13. Six patients showed adolescence or adulthood-onset dystonia. Seven patients presented with parkinsonism and 3 with myoclonus. Dysarthria was observed in 19 patients. Mild and moderate ID were present in 10 and 2 patients, respectively. CONCLUSION: We highlighted a mild GNAO1-related phenotype, including adolescent-onset dystonia, broadening the clinical spectrum of this condition. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Distonía , Trastornos Distónicos , Subunidades alfa de la Proteína de Unión al GTP Gi-Go , Trastornos del Movimiento , Trastornos Parkinsonianos , Distonía/genética , Trastornos Distónicos/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Humanos , Trastornos del Movimiento/genética , Trastornos Parkinsonianos/genética , FenotipoAsunto(s)
COVID-19 , Reumatología , Educación de Postgrado en Medicina , Becas , Humanos , Pandemias , Reumatología/educación , Estados UnidosRESUMEN
Most strategies to treat obesity-related disorders have involved prevention of diet-induced weight gain in lean mice. Treatment of obese individuals will require therapies that reverse the detrimental effects of excess body weight. Cyclin-dependent kinases have been shown to contribute to obesity and its adverse complications. Here, we show that roscovitine; a an orally available cyclin-dependent kinase inhibitor; given to male mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation/fibrosis as well as restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that roscovitine suppressed expression of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. It also identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases, AGC kinases and CAMK kinases. Pathway enrichment analysis showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and creatine biosynthesis are enriched following roscovitine treatment. For brown adipose tissue (BAT), analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups, AGC and CMGC kinases. Among the top enriched pathways were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling. We conclude that roscovitine is effective at preventing prolonged diet-induced metabolic disruption and restoring mitochondrial activity in BAT and eWAT.