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1.
Trends Genet ; 39(5): 415-429, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36842900

RESUMO

Herein we focus on connections between genetics and some central disorders of hypersomnolence - narcolepsy types 1 and 2 (NT1, NT2), idiopathic hypersomnia (IH), and Kleine-Levin syndrome (KLS) - for a better understanding of their etiopathogenetic mechanisms and a better diagnostic and therapeutic definition. Gene pleiotropism influences neurological and sleep disorders such as hypersomnia; therefore, genetics allows us to uncover common pathways to different pathologies, with potential new therapeutic perspectives. An important body of evidence has accumulated on NT1 and IH, allowing a better understanding of etiopathogenesis, disease biomarkers, and possible new therapeutic approaches. Further studies are needed in the field of epigenetics, which has a potential role in the modulation of biological specific hypersomnia pathways.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Hipersonia Idiopática , Narcolepsia , Humanos , Distúrbios do Sono por Sonolência Excessiva/genética , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Narcolepsia/genética , Narcolepsia/diagnóstico , Narcolepsia/tratamento farmacológico , Hipersonia Idiopática/diagnóstico , Hipersonia Idiopática/tratamento farmacológico , Hipersonia Idiopática/genética , Epigênese Genética/genética
2.
Proc Natl Acad Sci U S A ; 120(19): e2220911120, 2023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-37126681

RESUMO

Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin (PDYN) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT, PDYN, and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.


Assuntos
Cataplexia , Narcolepsia , Neuropeptídeos , Camundongos , Animais , Orexinas/metabolismo , Cataplexia/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neuropeptídeos/metabolismo , Narcolepsia/genética , Hipotálamo/metabolismo , Epigênese Genética , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo
3.
Proc Natl Acad Sci U S A ; 119(35): e2207531119, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-35994639

RESUMO

Narcolepsy type 1 (NT1) is a sleep disorder caused by a loss of orexinergic neurons. Narcolepsy type 2 (NT2) is heterogeneous; affected individuals typically have normal orexin levels. Following evaluation in mice, the effects of the orexin 2 receptor (OX2R)-selective agonist danavorexton were evaluated in single- and multiple-rising-dose studies in healthy adults, and in individuals with NT1 and NT2. In orexin/ataxin-3 narcolepsy mice, danavorexton reduced sleep/wakefulness fragmentation and cataplexy-like episodes during the active phase. In humans, danavorexton administered intravenously was well tolerated and was associated with marked improvements in sleep latency in both NT1 and NT2. In individuals with NT1, danavorexton dose-dependently increased sleep latency in the Maintenance of Wakefulness Test, up to the ceiling effect of 40 min, in both the single- and multiple-rising-dose studies. These findings indicate that OX2Rs remain functional despite long-term orexin loss in NT1. OX2R-selective agonists are a promising treatment for both NT1 and NT2.


Assuntos
Estimulantes do Sistema Nervoso Central , Narcolepsia , Receptores de Orexina , Adulto , Animais , Ataxina-3/genética , Ataxina-3/metabolismo , Cataplexia/tratamento farmacológico , Cataplexia/genética , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Modelos Animais de Doenças , Humanos , Camundongos , Narcolepsia/tratamento farmacológico , Narcolepsia/genética , Neurônios/metabolismo , Receptores de Orexina/agonistas , Receptores de Orexina/genética , Receptores de Orexina/metabolismo , Receptores de Orexina/uso terapêutico , Orexinas/genética , Orexinas/metabolismo , Fenótipo , Vigília/efeitos dos fármacos , Vigília/genética
4.
Neurogenetics ; 25(2): 79-83, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38240911

RESUMO

Narcolepsy with cataplexy is a complex disease with both genetic and environmental risk factors. To gain further insight into the homozygous HCRT-related narcolepsy, we present a case series of five patients from two consanguineous families, each harboring a novel homozygous variant of HCRT c.17_18del. All affected individuals exhibited severe cataplexy accompanied by narcolepsy symptoms during infancy. Additionally, cataplexy symptoms improved or disappeared in the majority of patients over time. Pathogenic variants in HCRT cause autosomal recessive narcolepsy with cataplexy. Genetic testing of the HCRT gene should be conducted in specific subgroups of narcolepsy, particularly those with early onset, familial cases, and a predominantly cataplexy phenotype.


Assuntos
Narcolepsia , Linhagem , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Alelos , Cataplexia/genética , Consanguinidade , Genes Recessivos , Homozigoto , Mutação/genética , Narcolepsia/genética , Orexinas/genética , Fenótipo
5.
J Autoimmun ; 146: 103234, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38663202

RESUMO

Narcolepsy is a rare cause of hypersomnolence and may be associated or not with cataplexy, i.e. sudden muscle weakness. These forms are designated narcolepsy-type 1 (NT1) and -type 2 (NT2), respectively. Notable characteristics of narcolepsy are that most patients carry the HLA-DQB1*06:02 allele and NT1-patients have strongly decreased levels of hypocretin-1 (synonym orexin-A) in the cerebrospinal fluid (CSF). The pathogenesis of narcolepsy is still not completely understood but the strong HLA-bias and increased frequencies of CD4+ T cells reactive to hypocretin in the peripheral blood suggest autoimmune processes in the hypothalamus. Here we analyzed the transcriptomes of CSF-cells from twelve NT1 and two NT2 patients by single cell RNAseq (scRNAseq). As controls, we used CSF cells from patients with multiple sclerosis, radiologically isolated syndrome, and idiopathic intracranial hypertension. From 27,255 CSF cells, we identified 20 clusters of different cell types and found significant differences in three CD4+ T cell and one monocyte clusters between narcolepsy and multiple sclerosis patients. Over 1000 genes were differentially regulated between patients with NT1 and other diseases. Surprisingly, the most strongly upregulated genes in narcolepsy patients as compared to controls were coding for the genome-encoded MTRNR2L12 and MTRNR2L8 peptides, which are homologous to the mitochondria-encoded HUMANIN peptide that is known playing a role in other neurological diseases including Alzheimer's disease.


Assuntos
Narcolepsia , Análise de Célula Única , Transcriptoma , Humanos , Narcolepsia/genética , Narcolepsia/líquido cefalorraquidiano , Masculino , Feminino , Adulto , Orexinas/líquido cefalorraquidiano , Orexinas/genética , Perfilação da Expressão Gênica , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Cadeias beta de HLA-DQ/genética , Pessoa de Meia-Idade , Adulto Jovem
6.
Ann Neurol ; 94(4): 762-771, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37395722

RESUMO

OBJECTIVE: Narcolepsy type 1 (NT1) is assumed to be caused solely by a lack of hypocretin (orexin) neurotransmission. Recently, however, we found an 88% reduction in corticotropin-releasing hormone (CRH)-positive neurons in the paraventricular nucleus (PVN). We assessed the remaining CRH neurons in NT1 to determine whether they co-express vasopressin (AVP) to reflect upregulation. We also systematically assessed other wake-systems, since current NT1 treatments target histamine, dopamine, and norepinephrine pathways. METHODS: In postmortem tissue of people with NT1 and matched controls, we immunohistochemically stained and quantified neuronal populations expressing: CRH and AVP in the PVN, and CRH in the Barrington nucleus; the key neuronal histamine-synthesizing enzyme, histidine decarboxylase (HDC) in the hypothalamic tuberomammillary nucleus (TMN); the rate-limited-synthesizing enzyme, tyrosine hydroxylase (TH), for dopamine in the mid-brain and for norepinephrine in the locus coeruleus (LC). RESULTS: In NT1, there was: a 234% increase in the percentage of CRH cells co-expressing AVP, while there was an unchanged integrated optical density of CRH staining in the Barrington nucleus; a 36% increased number of histamine neurons expressing HDC, while the number of typical human TMN neuronal profiles was unchanged; a tendency toward an increased density of TH-positive neurons in the substantia nigra compacta; while the density of TH-positive LC neurons was unchanged. INTERPRETATION: Our findings suggest an upregulation of activity by histamine neurons and remaining CRH neurons in NT1. This may explain earlier reports of normal basal plasma cortisol levels but lower levels after dexamethasone suppression. Alternatively, CRH neurons co-expressing AVP neurons are less vulnerable. ANN NEUROL 2023;94:762-771.


Assuntos
Arginina Vasopressina , Narcolepsia , Humanos , Dopamina , Histamina , Hormônio Liberador da Corticotropina , Norepinefrina/metabolismo , Narcolepsia/genética
7.
Int J Immunogenet ; 51(3): 187-191, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38462594

RESUMO

Narcolepsy is a life-long neurological disorder with well-established genetic risk factors. Human leukocyte antigen-DQB1*06:02 remains the strongest genetic predeterminant; however, polymorphisms in genes encoding the T-cell receptor alpha chain are also strongly linked. This case report shows the inheritance pathway of these genetic markers contributing to narcolepsy onset in a 17-year-old female.


Assuntos
Predisposição Genética para Doença , Cadeias beta de HLA-DQ , Homozigoto , Narcolepsia , Humanos , Feminino , Narcolepsia/genética , Narcolepsia/imunologia , Cadeias beta de HLA-DQ/genética , Adolescente , Polimorfismo Genético , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linhagem
8.
J Pharmacol Exp Ther ; 385(3): 193-204, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37001988

RESUMO

Loss of orexin neurons is associated with narcolepsy type 1 (NT1), which is characterized by multiple symptoms including excessive daytime sleepiness and cataplexy. Orexin 2 receptor (OX2R) knockout (KO) mice, but not orexin 1 receptor (OX1R) KO mice, show narcolepsy-like phenotypes, thus OX2R agonists are potentially promising for treating NT1. In fact, in early proof-of-concept studies, intravenous infusion of danavorexton, an OX2R-selective agonist, significantly increased wakefulness in individuals with NT1. However, danavorexton has limited oral availability. Here, we report pharmacological characteristics of a novel OX2R agonist, TAK-994 [N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluorobiphenyl-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide sesquihydrate]. TAK-994 activated recombinant human OX2R (EC50 value of 19 nM) with > 700-fold selectivity against OX1R and activated OX2R-downstream signaling similar to those by orexin peptides in vitro. Oral administration of TAK-994 promoted wakefulness in normal mice but not in OX2R KO mice. TAK-994 also ameliorated narcolepsy-like symptoms in two mouse models of narcolepsy: orexin/ataxin-3 mice and orexin-tTA;TetO diphtheria toxin A mice. The wake-promoting effects of TAK-994 in orexin/ataxin-3 mice were maintained after chronic dosing for 14 days. These data suggest that overall in vitro and in vivo properties, except oral availability, are very similar between TAK-994 and danavorexton. Preclinical characteristics of TAK-994 shown here, together with upcoming clinical study results, can improve our understanding for orally available OX2R agonists as new therapeutic drugs for NT1 and other hypersomnia disorders. SIGNIFICANCE STATEMENT: Narcolepsy type 1 (NT1) is caused by a loss of orexin neurons, and thus an orexin 2 receptor (OX2R) agonist is considered to address the underlying pathophysiology of NT1. Oral administration of TAK-994, a novel OX2R agonist, promoted wakefulness in normal mice, but not in OX2R knockout mice, and ameliorated fragmentation of wakefulness and cataplexy-like episodes in mouse models of narcolepsy. These findings indicate that TAK-994 is an orally available brain-penetrant OX2R-selective agonist with potential to improve narcolepsy-like symptoms.


Assuntos
Cataplexia , Narcolepsia , Camundongos , Humanos , Animais , Cataplexia/tratamento farmacológico , Vigília , Ataxina-3 , Sono/genética , Narcolepsia/tratamento farmacológico , Narcolepsia/genética , Orexinas/genética , Orexinas/metabolismo , Orexinas/farmacologia , Encéfalo/metabolismo , Camundongos Knockout , Receptores de Orexina/agonistas , Receptores de Orexina/genética , Receptores de Orexina/uso terapêutico
9.
J Neurosci ; 41(7): 1582-1596, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33372061

RESUMO

During rapid eye movement (REM) sleep, anti-gravity muscle tone and bodily movements are mostly absent, because somatic motoneurons are inhibited by descending inhibitory pathways. Recent studies showed that glycine/GABA neurons in the ventromedial medulla (VMM; GlyVMM neurons) play an important role in generating muscle atonia during REM sleep (REM-atonia). However, how these REM-atonia-inducing neurons interconnect with other neuronal populations has been unknown. In the present study, we first identified a specific subpopulation of GlyVMM neurons that play an important role in induction of REM-atonia by virus vector-mediated tracing in male mice in which glycinergic neurons expressed Cre recombinase. We found these neurons receive direct synaptic input from neurons in several brain stem regions, including glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD; GluSLD neurons). Silencing this circuit by specifically expressing tetanus toxin light chain (TeTNLC) resulted in REM sleep without atonia. This manipulation also caused a marked decrease in time spent in cataplexy-like episodes (CLEs) when applied to narcoleptic orexin-ataxin-3 mice. We also showed that GlyVMM neurons play an important role in maintenance of sleep. This present study identified a population of glycinergic neurons in the VMM that are commonly involved in REM-atonia and cataplexy.SIGNIFICANCE STATEMENT We identified a population of glycinergic neurons in the ventral medulla that plays an important role in inducing muscle atonia during rapid eye movement (REM) sleep. It sends axonal projections almost exclusively to motoneurons in the spinal cord and brain stem except to those that innervate extraocular muscles, while other glycinergic neurons in the same region also send projections to other regions including monoaminergic nuclei. Furthermore, these neurons receive direct inputs from several brainstem regions including glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD). Genetic silencing of this pathway resulted in REM sleep without atonia and a decrease of cataplexy when applied to narcoleptic mice. This work identified a neural population involved in generating muscle atonia during REM sleep and cataplexy.


Assuntos
Cataplexia/fisiopatologia , Glicina/fisiologia , Bulbo/fisiologia , Músculo Esquelético/fisiologia , Neurônios/fisiologia , Sono REM/fisiologia , Animais , Ataxina-3/genética , Axônios/fisiologia , Cataplexia/genética , Eletroencefalografia , Masculino , Bulbo/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Tono Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Narcolepsia/genética , Narcolepsia/fisiopatologia , Orexinas/genética , Toxina Tetânica/farmacologia
10.
Hum Mol Genet ; 29(11): 1864-1881, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-31984424

RESUMO

ADCA-DN and HSN-IE are rare neurodegenerative syndromes caused by dominant mutations in the replication foci targeting sequence (RFTS) of the DNA methyltransferase 1 (DNMT1) gene. Both phenotypes resemble mitochondrial disorders, and mitochondrial dysfunction was first observed in ADCA-DN. To explore mitochondrial involvement, we studied the effects of DNMT1 mutations in fibroblasts from four ADCA-DN and two HSN-IE patients. We documented impaired activity of purified DNMT1 mutant proteins, which in fibroblasts results in increased DNMT1 amount. We demonstrated that DNMT1 is not localized within mitochondria, but it is associated with the mitochondrial outer membrane. Concordantly, mitochondrial DNA failed to show meaningful CpG methylation. Strikingly, we found activated mitobiogenesis and OXPHOS with significant increase of H2O2, sharply contrasting with a reduced ATP content. Metabolomics profiling of mutant cells highlighted purine, arginine/urea cycle and glutamate metabolisms as the most consistently altered pathways, similar to primary mitochondrial diseases. The most severe mutations showed activation of energy shortage AMPK-dependent sensing, leading to mTORC1 inhibition. We propose that DNMT1 RFTS mutations deregulate metabolism lowering ATP levels, as a result of increased purine catabolism and urea cycle pathways. This is associated with a paradoxical mitochondrial hyper-function and increased oxidative stress, possibly resulting in neurodegeneration in non-dividing cells.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/genética , Predisposição Genética para Doença , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Degeneração Neural/genética , Ataxias Espinocerebelares/genética , Metilação de DNA/genética , Surdez/genética , Surdez/fisiopatologia , Feminino , Fibroblastos/metabolismo , Neuropatias Hereditárias Sensoriais e Autônomas/fisiopatologia , Humanos , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação/genética , Narcolepsia/genética , Narcolepsia/fisiopatologia , Degeneração Neural/fisiopatologia , Fosforilação Oxidativa , Fenótipo , Processamento de Proteína Pós-Traducional/genética , Ataxias Espinocerebelares/fisiopatologia
11.
BMC Neurol ; 22(1): 439, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401198

RESUMO

BACKGROUND: Narcolepsy type 1 (NT1) is a rare and chronic neurological disease characterized by sudden sleep attacks, overwhelming daytime drowsiness, and cataplexy. When associated with a sudden loss of muscle tone (cataplexy) narcolepsy is classified as type 1, while the absence of cataplexy indicates type 2. Genetic, degenerative, and immunological hypotheses to explain the pathophysiology of NT1 are still a matter of debate. To contribute to the understanding of NT1 genetic basis, here we describe, for the first time, a whole genome analysis of a monozygotic twin pair discordant for NT1. CASE PRESENTATION: We present the case of a pair of 17-year-old male, monozygotic twins discordant for NT1. The affected twin had Epworth Sleepiness Scale (ESS) of 20 (can range from 0 to 24), cataplexy, hypnagogic hallucinations, polysomnography without abnormalities, multiple sleep latency tests (MSLT) positive for narcolepsy, a mean sleep latency of 3 min, sleep-onset REM periods SOREMPs of 5, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of zero pg/mL (normal values are > 200 pg/mL). The other twin had no narcolepsy symptoms (ESS of 4), normal polysomnography, MSLT without abnormalities, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of 396,74 pg/mL. To describe the genetic background for the NT1 discordant manifestations in this case, we present the whole-genome analysis of this monozygotic twin pair. The whole-genome comparison revealed that both twins have identical NT1 pathogenic mutations in known genes, such as HLA-DQB1*06:02:01, HLA-DRB1*11:01:02/*15:03:01. The affected twin has the expected clinical manifestation while the unaffected twin has an unexpected phenotype. The unaffected twin has significantly more frameshift mutations as compared to the affected twin (108 versus 75) and mutations that affect stop codons (61 versus 5 in stop gain, 26 versus 2 in start lost). CONCLUSIONS: The differences observed in frameshift and stop codon mutations in the unaffected twin are consistent with loss-of-function effects and protective alleles, that are almost always associated with loss-of-function rare alleles. Also, overrepresentation analysis of genes containing variants with potential clinical relevance in the unaffected twin shows that most mutations are in genes related to immune regulation function, Golgi apparatus, MHC, and olfactory receptor. These observations support the hypothesis that NT1 has an immunological basis although protective mutations in non-HLA alleles might interfere with the expression of the NT1 phenotype and consequently, with the clinical manifestation of the disease.


Assuntos
Cataplexia , Narcolepsia , Masculino , Humanos , Orexinas , Brasil , Narcolepsia/diagnóstico , Narcolepsia/genética , Polissonografia
12.
Acta Paediatr ; 111(4): 820-824, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33566388

RESUMO

AIM: Paediatric acute-onset neuropsychiatric syndrome (PANS) is defined by an acute onset of obsessive-compulsive disorder and/or eating restrictions and at least two other severe neuropsychiatric symptoms. The condition is suspected to have an immune-mediated pathophysiology, but reliable biomarkers have not been identified. METHODS: We hypothesised that PANS, like narcolepsy, might have a human leucocyte antigen (HLA) association, as found in 95% of children developing narcolepsy after H1N1 immunisation. Low resolution genotyping of the MHC class II antigens HLA-DRB1 and HLA-DQB1 was performed using two different PCR-based methods. In addition, parents were interviewed regarding a detailed family history of autoimmune diseases in first-degree relatives. A total of 18 children, aged 5-14 (mean 8.2) years at onset of PANS met symptom criteria. RESULTS: No evident association between PANS and the specific HLA alleles examined was observed. In first-degree relatives of 10 of the 18 children, an autoimmune disease had been diagnosed, and three of the 18 children themselves had an autoimmune disease. CONCLUSION: No HLA allele association such as seen in children with narcolepsy after H1N1 immunisation could be confirmed in this group of children with PANS. However, more than half the group had a first-degree relative with a diagnosed autoimmune disease.


Assuntos
Doenças Autoimunes , Vírus da Influenza A Subtipo H1N1 , Narcolepsia , Transtorno Obsessivo-Compulsivo , Infecções Estreptocócicas , Doenças Autoimunes/complicações , Doenças Autoimunes/genética , Autoimunidade , Criança , Humanos , Narcolepsia/complicações , Narcolepsia/genética , Transtorno Obsessivo-Compulsivo/complicações , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/genética , Infecções Estreptocócicas/diagnóstico
13.
Int J Neurosci ; 132(7): 706-713, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33045884

RESUMO

INTRODUCTION: Narcolepsy is a chronic neurological and a genetic disorder of autoimmune origin, which is characterized by five main symptoms, including excessive day time sleepiness, sudden loss of muscle tone or cataplexy, sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. While there are several diagnostic tests for Narcolepsy such as MSLT (mean sleep latency test), polysomnography and low range of hypocretin in cerebrospinal fluid (CSF), sensitivity and specificity in these methodologies are not sufficient enough. Therefore, methods with higher sensitivity for the accurate diagnosis and confirmation of the disease are necessary. METHODS: According to the infrequent prevalence of narcolepsy disease, we scheduled a case-control association study with 20 narcoleptic patients and 150 healthy individuals in a high-resolution HLA typing procedure employing SSP-PCR. RESULTS: Our study demonstrates that the DQB1*06:02 allele provides the highest susceptibility with absolute risk of 0.13%, for Narcolepsy (P = 1x10-14, RR = 60.5, PcPPV = 0.13%), while, HLA-DQB1* 03:05 allele presents protection to Narcolepsy (P = 1x10-4, PcPPV = 3.19x10-4%). Furthermore, for the first time, the AA analysis displayed that AA serine182 and threonine185 located on epitope of DQß1 chain receptor (DQB1Ser182,Thr185) present significant susceptibility for Narcolepsy (Pc= 87.03 × 10-13, PcPPV = 0.024%) while, asparagine182 located on epitope of DQß1 protein receptor (DQB1Asn182) confers the highest protection against development of Narcolepsy (Pc= 2.16 × 10-5, PcPPV = 0.0012%). CONCLUSION: Thus, this can be proposed that the polymorphic differences in the epitope of the HLA receptor could contribute to their differential association with the Narcolepsy in Iranian population.


Assuntos
Aminoácidos , Cadeias beta de HLA-DQ , Narcolepsia , Asparagina , Epitopos , Cadeias beta de HLA-DQ/genética , Humanos , Irã (Geográfico) , Narcolepsia/diagnóstico , Narcolepsia/genética
14.
J Neurosci ; 39(47): 9435-9452, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31628177

RESUMO

Narcolepsy, characterized by excessive daytime sleepiness, is associated with dysfunction of the hypothalamic hypocretin/orexin (Hcrt) system, either due to extensive loss of Hcrt cells (Type 1, NT1) or hypothesized Hcrt signaling impairment (Type 2, NT2). Accordingly, efforts to recapitulate narcolepsy-like symptoms in mice have involved ablating these cells or interrupting Hcrt signaling. Here, we describe orexin/Arch mice, in which a modified archaerhodopsin-3 gene was inserted downstream of the prepro-orexin promoter, resulting in expression of the yellow light-sensitive Arch-3 proton pump specifically within Hcrt neurons. Histological examination along with ex vivo and in vivo electrophysiological recordings of male and female orexin/Arch mice demonstrated silencing of Hcrt neurons when these cells were photoilluminated. However, high expression of the Arch transgene affected cellular and physiological parameters independent of photoillumination. The excitability of Hcrt neurons was reduced, and both circadian and metabolic parameters were perturbed in a subset of orexin/Arch mice that exhibited high levels of Arch expression. Orexin/Arch mice also had increased REM sleep under baseline conditions but did not exhibit cataplexy, a sudden loss of muscle tone during wakefulness characteristic of NT1. These aberrations resembled some aspects of mouse models with Hcrt neuron ablation, yet the number of Hcrt neurons in orexin/Arch mice was not reduced. Thus, orexin/Arch mice may be useful to investigate Hcrt system dysfunction when these neurons are intact, as is thought to occur in narcolepsy without cataplexy (NT2). These results also demonstrate the utility of extended phenotypic screening of transgenic models when specific neural circuits have been manipulated.SIGNIFICANCE STATEMENT Optogenetics has become an invaluable tool for functional dissection of neural circuitry. While opsin expression is often achieved by viral injection, stably integrated transgenes offer some practical advantages. Here, we demonstrate successful transgenic expression of an inhibitory opsin in hypocretin/orexin neurons, which are thought to promote or maintain wakefulness. Both brief and prolonged illumination resulted in inhibition of these neurons and induced sleep. However, even in the absence of illumination, these cells exhibited altered electrical characteristics, particularly when transgene expression was high. These aberrant properties affected metabolism and sleep, resulting in a phenotype reminiscent of the narcolepsy Type 2, a sleep disorder for which no good animal model currently exists.


Assuntos
Proteínas Arqueais/biossíntese , Encéfalo/metabolismo , Narcolepsia/metabolismo , Neurônios/metabolismo , Orexinas/metabolismo , Animais , Proteínas Arqueais/genética , Encéfalo/citologia , Química Encefálica/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Narcolepsia/genética , Neurônios/química , Optogenética/métodos , Orexinas/genética , Técnicas de Cultura de Órgãos
15.
J Sleep Res ; 29(6): e12982, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31943460

RESUMO

PAX6 gene mutations cause a variety of eye and central nervous system (CNS) abnormalities. Aniridia is often accompanied by CNS abnormalities such as pineal gland atrophy or hypoplasia, leading to disturbed circadian rhythm and sleep disorders. Less is known on the coincidence of narcolepsy in this patient group. We aimed to find out whether the circadian rhythm or sleep-wake structure was affected in patients with aniridia. Four members of a family segregating with congenital aniridia in two generations were included in the study. The patients were subjected to genetic testing for a PAX6 mutation, multiple sleep latency test, whole-brain magnetic resonance imaging (MRI), hypocretin-1 in cerebrospinal fluid, and Human Leukocyte Antigen DQ beta1*06:02. All four members were heterozygous for the pathogenic c.959-1G>A mutation in the PAX6 gene. Sleep disturbance was observed in all family members. The index patient was diagnosed with narcolepsy. MRI showed a hypoplastic pineal gland in all members. We describe the first case of a patient with PAX6 haploinsufficiency, aniridia and pineal gland hypoplasia diagnosed with narcolepsy type-1, suggesting a complex sleep disorder pathogenesis.


Assuntos
Aniridia/genética , Narcolepsia/genética , Fator de Transcrição PAX6/genética , Adulto , Aniridia/complicações , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Adulto Jovem
16.
Int J Med Sci ; 17(11): 1508-1514, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32669953

RESUMO

Aims: To investigate the interactions among narcolepsy-associated genes and reveal the pathways these genes involved through bioinformatics analyses. Methods: The study was performed with the following steps: 1) Selected the previously discovered narcolepsy risk genes through literature review, 2) pathway enrichment analysis, and construction of gene-gene and protein-protein interaction (PPI) networks for narcolepsy. Results: 1) GO analysis revealed the positive regulation of interferon-gamma production as the most enriched terms in biological process, and C-C chemokine receptor activity as the most enriched term in molecular function, 2) KEGG pathway enrichment analysis revealed selective enrichment of genes in cytokine-cytokine receptor interaction signaling pathways, and 3) five hub genes were identified (IFNAR1, IL10RB, DNMT1, TNFSF4 and NFATC2). Conclusion: The bioinformatics results provide new insights into the molecular pathogenesis of narcolepsy and the identification of potential therapeutic targets for narcolepsy treatment.


Assuntos
Redes Reguladoras de Genes/fisiologia , Narcolepsia/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Ontologia Genética , Redes Reguladoras de Genes/genética , Humanos , Mapas de Interação de Proteínas/genética , Mapas de Interação de Proteínas/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
17.
Med Res Rev ; 39(3): 961-975, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30426515

RESUMO

Narcolepsy is a rare, chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, vivid hallucinations, and sleep paralysis. Narcolepsy occurs in approximately 1 of 3000 people, affecting mainly adolescents aged 15 to 30 years. Recently, people with narcolepsy were shown to exhibit extensive orexin/hypocretin neuronal loss. The orexin system regulates sleep/wake control via complex interactions with monoaminergic, cholinergic and GABA-ergic neuronal systems. Currently, no cure for narcolepsy exists, but some symptoms can be controlled with medication (eg, stimulants, antidepressants, etc). Orexin supplementation represents a more sophisticated way to treat narcolepsy because it addresses the underlying cause of the disease and not just the symptoms. Research on orexin supplementation in the treatment of sleep disorders has strongly increased over the past two decades. This review focuses on a brief description of narcolepsy, the mechanisms by which the orexin system regulates sleep/wake cycles, and finally, possible therapeutic options based on orexin supplementation in animal models and patients with narcolepsy.


Assuntos
Narcolepsia/tratamento farmacológico , Orexinas/uso terapêutico , Animais , Transplante de Células , Terapia Genética , Humanos , Narcolepsia/genética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
18.
J Autoimmun ; 100: 1-6, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30948158

RESUMO

Convergent evidence points to the involvement of T cells in the pathogenesis of narcolepsy type 1 (NT1). Here, we hypothesized that expanded disease-specific T cell clones could be detected in the blood of NT1 patients. We compared the TCR repertoire of circulating antigen-experienced CD4+ and CD8+ T cells from 13 recently diagnosed NT1 patients and 11 age-, sex-, and HLA-DQB1*06:02-matched healthy controls. We detected a bias in the usage of TRAV3 and TRAV8 families, with public CDR3α motifs only present in CD4+ T cells from patients with NT1. These findings may offer a unique tool to identify disease-relevant antigens.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Narcolepsia , Receptores de Antígenos de Linfócitos T , Adolescente , Adulto , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Cadeias beta de HLA-DQ/genética , Cadeias beta de HLA-DQ/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Narcolepsia/genética , Narcolepsia/imunologia , Narcolepsia/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia
20.
Sleep Breath ; 23(1): 303-309, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30187366

RESUMO

BACKGROUND: Narcolepsy is an uncommon neurological disorder characterised by irresistible spells of sleep associated with abnormal rapid eye movement (REM) sleep. The association between narcolepsy and human leukocyte antigen HLA- DQB1*06:02 has been established elsewhere but remains to be investigated among Saudi Arabian patients with narcolepsy. METHODS: A total of 29 Saudi patients with type I or type 2 narcolepsy comprising of 23 (79%) males and 6 (21%) females with a mean age of 17.2 ± 9.6 years were included in this study. Type 1 or type 2 narcolepsy was diagnosed by full polysomnography followed by a multiple sleep latency test in accordance with International Classifications of Sleep Disorders-3 criteria. HLA typing for DQB1 alleles was performed by polymerase chain reaction and hybridization with sequence-specific oligonucleotide probes. Differences in clinical and sleep parameters were compared by univariable analyses. HLA-DQB1*06:02 frequency was systematically compared with the published literature. RESULTS: Type 1 narcolepsy was diagnosed in 19/29 (65.5%) patients, whereas 10/29 (34.5%) patients had type 2 narcolepsy. DQB1*06:02 was present in 25/29 (86.2%) patients; 15/19 (78.9%) narcolepsy type 1 patients and 10/10 (100%) narcolepsy type 2 patients harboured the DQB1*06:02 allele. REM latency was significantly lower in DQB1*06:02-positive patients compared to DQB1*06:02-negative patients (17.6 ± 32.3 min vs. 106.0 ± 86.0 min; p = 0.025). Epworth Sleepiness Scale scores were significantly higher among type 1 than type 2 narcolepsy patients (19.7 ± 3.2 vs 15.3 ± 3.6; p = 0.02). CONCLUSIONS: DQB1*06:02 allele frequencies among Saudi patients with narcolepsy were consistent with previously published data.


Assuntos
Árabes/genética , Frequência do Gene/genética , Cadeias beta de HLA-DQ/genética , Narcolepsia/genética , Polissonografia , Adolescente , Adulto , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Narcolepsia/diagnóstico , Arábia Saudita , Adulto Jovem
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