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1.
Annu Rev Genomics Hum Genet ; 25(1): 259-285, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38669479

RESUMEN

Healthy sleep is vital for humans to achieve optimal health and longevity. Poor sleep and sleep disorders are strongly associated with increased morbidity and mortality. However, the importance of good sleep continues to be underrecognized. Mechanisms regulating sleep and its functions in humans remain mostly unclear even after decades of dedicated research. Advancements in gene sequencing techniques and computational methodologies have paved the way for various genetic analysis approaches, which have provided some insights into human sleep genetics. This review summarizes our current knowledge of the genetic basis underlying human sleep traits and sleep disorders. We also highlight the use of animal models to validate genetic findings from human sleep studies and discuss potential molecular mechanisms and signaling pathways involved in the regulation of human sleep.


Asunto(s)
Trastornos del Sueño-Vigilia , Sueño , Humanos , Trastornos del Sueño-Vigilia/genética , Sueño/genética , Animales , Transducción de Señal/genética
2.
Proc Natl Acad Sci U S A ; 121(9): e2320276121, 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38381789

RESUMEN

Neuropeptide S (NPS) was postulated to be a wake-promoting neuropeptide with unknown mechanism, and a mutation in its receptor (NPSR1) causes the short sleep duration trait in humans. We investigated the role of different NPS+ nuclei in sleep/wake regulation. Loss-of-function and chemogenetic studies revealed that NPS+ neurons in the parabrachial nucleus (PB) are wake-promoting, whereas peri-locus coeruleus (peri-LC) NPS+ neurons are not important for sleep/wake modulation. Further, we found that a NPS+ nucleus in the central gray of the pons (CGPn) strongly promotes sleep. Fiber photometry recordings showed that NPS+ neurons are wake-active in the CGPn and wake/REM-sleep active in the PB and peri-LC. Blocking NPS-NPSR1 signaling or knockdown of Nps supported the function of the NPS-NPSR1 pathway in sleep/wake regulation. Together, these results reveal that NPS and NPS+ neurons play dichotomous roles in sleep/wake regulation at both the molecular and circuit levels.


Asunto(s)
Neuropéptidos , Sueño , Humanos , Sueño/fisiología , Puente/fisiología , Locus Coeruleus/fisiología , Neuronas/metabolismo , Neuropéptidos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo
3.
Proc Natl Acad Sci U S A ; 120(15): e2221686120, 2023 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-37014857

RESUMEN

Sleep is essential for our well-being, and chronic sleep deprivation has unfavorable health consequences. We recently demonstrated that two familial natural short sleep (FNSS) mutations, DEC2-P384R and Npsr1-Y206H, are strong genetic modifiers of tauopathy in PS19 mice, a model of tauopathy. To gain more insight into how FNSS variants modify the tau phenotype, we tested the effect of another FNSS gene variant, Adrb1-A187V, by crossing mice with this mutation onto the PS19 background. We found that the Adrb1-A187V mutation helped restore rapid eye movement (REM) sleep and alleviated tau aggregation in a sleep-wake center, the locus coeruleus (LC), in PS19 mice. We found that ADRB1+ neurons in the central amygdala (CeA) sent projections to the LC, and stimulating CeAADRB1+ neuron activity increased REM sleep. Furthermore, the mutant Adrb1 attenuated tau spreading from the CeA to the LC. Our findings suggest that the Adrb1-A187V mutation protects against tauopathy by both mitigating tau accumulation and attenuating tau spreading.


Asunto(s)
Trastornos del Sueño-Vigilia , Tauopatías , Ratones , Animales , Sueño REM , Tauopatías/genética , Sueño/fisiología , Locus Coeruleus/metabolismo , Receptores Adrenérgicos , Proteínas tau/genética , Proteínas tau/metabolismo , Ratones Transgénicos , Modelos Animales de Enfermedad
4.
Proc Natl Acad Sci U S A ; 119(34): e2203266119, 2022 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-35901245

RESUMEN

Sleep is a necessity for our survival, but its regulation remains incompletely understood. Here, we used a human sleep duration gene to identify a population of cells in the peri-tegmental reticular nucleus (pTRNADRB1) that regulate sleep-wake, uncovering a role for a poorly understood brain area. Although initial ablation in mice led to increased wakefulness, further validation revealed that pTRNADRB1 neuron stimulation strongly promotes wakefulness, even after stimulation offset. Using combinatorial genetics, we found that excitatory pTRNADRB1 neurons promote wakefulness. pTRN neurons can be characterized as anterior- or posterior-projecting neurons based on multiplexed analysis of projections by sequencing (MAPseq) analysis. Finally, we found that pTRNADRB1 neurons promote wakefulness, in part, through projections to the lateral hypothalamus. Thus, human genetic information from a human sleep trait allowed us to identify a role for the pTRN in sleep-wake regulation.


Asunto(s)
Sueño , Tegmento Mesencefálico , Vigilia , Animales , Humanos , Área Hipotalámica Lateral/fisiología , Ratones , Neuronas/fisiología , Sueño/fisiología , Tegmento Mesencefálico/fisiología , Vigilia/fisiología
5.
Mov Disord ; 39(3): 486-497, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38197134

RESUMEN

BACKGROUND: Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant ataxia with invariable sensory neuropathy originally described in a family with Swedish ancestry residing in Utah more than 25 years ago. Despite tight linkage to the 16q22 region, the molecular diagnosis has since remained elusive. OBJECTIVES: Inspired by pathogenic structural variation implicated in other 16q-ataxias with linkage to the same locus, we revisited the index SCA4 cases from the Utah family using novel technologies to investigate structural variation within the candidate region. METHODS: We adopted a targeted long-read sequencing approach with adaptive sampling on the Oxford Nanopore Technologies (ONT) platform that enables the detection of segregating structural variants within a genomic region without a priori assumptions about any variant features. RESULTS: Using this approach, we found a heterozygous (GGC)n repeat expansion in the last coding exon of the zinc finger homeobox 3 (ZFHX3) gene that segregates with disease, ranging between 48 and 57 GGC repeats in affected probands. This finding was replicated in a separate family with SCA4. Furthermore, the estimation of this GGC repeat size in short-read whole genome sequencing (WGS) data of 21,836 individuals recruited to the 100,000 Genomes Project in the UK and our in-house dataset of 11,258 exomes did not reveal any pathogenic repeats, indicating that the variant is ultrarare. CONCLUSIONS: These findings support the utility of adaptive long-read sequencing as a powerful tool to decipher causative structural variation in unsolved cases of inherited neurological disease. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Ataxia Cerebelosa , Ataxias Espinocerebelosas , Humanos , Linaje , Ataxias Espinocerebelosas/genética , Ataxia Cerebelosa/genética , Exones , Proteínas de Homeodominio/genética
6.
Cereb Cortex ; 33(8): 4293-4304, 2023 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-36030380

RESUMEN

Neocortical vasoactive intestinal polypeptide-expressing (VIP+) interneurons display highly diverse morpho-electrophysiological and molecular properties. To begin to understand the function of VIP+ interneurons in cortical circuits, they must be clearly and comprehensively classified into distinct subpopulations based on specific molecular markers. Here, we utilized patch-clamp RT-PCR (Patch-PCR) to simultaneously obtain the morpho-electric properties and mRNA profiles of 155 VIP+ interneurons in layers 2 and 3 (L2/3) of the mouse somatosensory cortex. Using an unsupervised clustering method, we identified 3 electrophysiological types (E-types) and 2 morphological types (M-types) of VIP+ interneurons. Joint clustering based on the combined electrophysiological and morphological features resulted in 3 morpho-electric types (ME-types). More importantly, we found these 3 ME-types expressed distinct marker genes: ~94% of Sncg+ cells were ME-type 1, 100% of Mybpc1+ cells were ME-type 2, and ~78% of Parm1+ were ME-type 3. By clarifying the properties of subpopulations of cortical L2/3 VIP+ interneurons, this study establishes a basis for future investigations aiming to elucidate their physiological roles.


Asunto(s)
Corteza Somatosensorial , Péptido Intestinal Vasoactivo , Animales , Ratones , Fenómenos Electrofisiológicos , Interneuronas/fisiología , Corteza Somatosensorial/fisiología , Péptido Intestinal Vasoactivo/metabolismo , Proteínas de Neoplasias/metabolismo , gamma-Sinucleína/metabolismo , Proteína de Unión a Andrógenos/metabolismo
7.
Proc Natl Acad Sci U S A ; 116(24): 12045-12053, 2019 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-31138685

RESUMEN

Many components of the circadian molecular clock are conserved from flies to mammals; however, the role of mammalian Timeless remains ambiguous. Here, we report a mutation in the human TIMELESS (hTIM) gene that causes familial advanced sleep phase (FASP). Tim CRISPR mutant mice exhibit FASP with altered photic entrainment but normal circadian period. We demonstrate that the mutation prevents TIM accumulation in the nucleus and has altered affinity for CRY2, leading to destabilization of PER/CRY complex and a shortened period in nonmature mouse embryonic fibroblasts (MEFs). We conclude that TIM, when excluded from the nucleus, can destabilize the negative regulators of the circadian clock, alter light entrainment, and cause FASP.


Asunto(s)
Proteínas de Ciclo Celular/genética , Relojes Circadianos/genética , Ritmo Circadiano/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación/genética , Sueño/genética , Animales , Línea Celular , Fibroblastos/fisiología , Células HEK293 , Humanos , Luz , Masculino , Ratones , Ratones Endogámicos C57BL
8.
Annu Rev Neurosci ; 36: 25-50, 2013 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-23642134

RESUMEN

Many neurologic diseases cause discrete episodic impairment in contrast with progressive deterioration. The symptoms of these episodic disorders exhibit striking variety. Herein we review what is known of the phenotypes, genetics, and pathophysiology of episodic neurologic disorders. Of these, most are genetically complex, with unknown or polygenic inheritance. In contrast, a fascinating panoply of episodic disorders exhibit Mendelian inheritance. We classify episodic Mendelian disorders according to the primary neuroanatomical location affected: skeletal muscle, cardiac muscle, neuromuscular junction, peripheral nerve, or central nervous system (CNS). Most known Mendelian mutations alter genes that encode membrane-bound ion channels. These mutations cause ion channel dysfunction, which ultimately leads to altered membrane excitability as manifested by episodic disease. Other Mendelian disease genes encode proteins essential for ion channel trafficking or stability. These observations have cemented the channelopathy paradigm, in which episodic disorders are conceptualized as disorders of ion channels. However, we expand on this paradigm to propose that dysfunction at the synaptic and neuronal circuit levels may underlie some episodic neurologic entities.


Asunto(s)
Mutación/genética , Enfermedades del Sistema Nervioso , Síntomas Afectivos/etiología , Animales , Sistema Nervioso Central/patología , Canalopatías/genética , Humanos , Músculo Esquelético/patología , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso/fisiopatología , Unión Neuromuscular/genética , Unión Neuromuscular/patología , Nervios Periféricos/patología
9.
Ann Neurol ; 88(4): 830-842, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32715519

RESUMEN

OBJECTIVE: The objective of this study was to identify the genetic cause for progressive peripheral nerve disease in a Venezuelan family. Despite the growing list of genes associated with Charcot-Marie-Tooth disease, many patients with axonal forms lack a genetic diagnosis. METHODS: A pedigree was constructed, based on family clinical data. Next-generation sequencing of mitochondrial DNA (mtDNA) was performed for 6 affected family members. Muscle biopsies from 4 family members were used for analysis of muscle histology and ultrastructure, mtDNA sequencing, and RNA quantification. Ultrastructural studies were performed on sensory nerve biopsies from 2 affected family members. RESULTS: Electrodiagnostic testing showed a motor and sensory axonal polyneuropathy. Pedigree analysis revealed inheritance only through the maternal line, consistent with mitochondrial transmission. Sequencing of mtDNA identified a mutation in the mitochondrial tRNAVal (mt-tRNAVal ) gene, m.1661A>G, present at nearly 100% heteroplasmy, which disrupts a Watson-Crick base pair in the T-stem-loop. Muscle biopsies showed chronic denervation/reinnervation changes, whereas biochemical analysis of electron transport chain (ETC) enzyme activities showed reduction in multiple ETC complexes. Northern blots from skeletal muscle total RNA showed severe reduction in abundance of mt-tRNAVal , and mildly increased mt-tRNAPhe , in subjects compared with unrelated age- and sex-matched controls. Nerve biopsies from 2 affected family members demonstrated ultrastructural mitochondrial abnormalities (hyperplasia, hypertrophy, and crystalline arrays) consistent with a mitochondrial neuropathy. CONCLUSION: We identify a previously unreported cause of Charcot-Marie-Tooth (CMT) disease, a mutation in the mt-tRNAVal , in a Venezuelan family. This work expands the list of CMT-associated genes from protein-coding genes to a mitochondrial tRNA gene. ANN NEUROL 2020;88:830-842.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , ARN Mitocondrial/genética , ARN de Transferencia/genética , Adolescente , Adulto , Anciano de 80 o más Años , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Venezuela , Adulto Joven
10.
Proc Natl Acad Sci U S A ; 115(13): 3434-3439, 2018 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-29531056

RESUMEN

Adequate sleep is essential for physical and mental health. We previously identified a missense mutation in the human DEC2 gene (BHLHE41) leading to the familial natural short sleep behavioral trait. DEC2 is a transcription factor regulating the circadian clock in mammals, although its role in sleep regulation has been unclear. Here we report that prepro-orexin, also known as hypocretin (Hcrt), gene expression is increased in the mouse model expressing the mutant hDEC2 transgene (hDEC2-P384R). Prepro-orexin encodes a precursor protein of a neuropeptide producing orexin A and B (hcrt1 and hcrt2), which is enriched in the hypothalamus and regulates maintenance of arousal. In cell culture, DEC2 suppressed prepro-orexin promoter-luc (ore-luc) expression through cis-acting E-box elements. The mutant DEC2 has less repressor activity than WT-DEC2, resulting in increased orexin expression. DEC2-binding affinity for the prepro-orexin gene promoter is decreased by the P384R mutation, likely due to weakened interaction with other transcription factors. In vivo, the decreased immobility time of the mutant transgenic mice is attenuated by an orexin receptor antagonist. Our results suggested that DEC2 regulates sleep/wake duration, at least in part, by modulating the neuropeptide hormone orexin.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Regulación de la Expresión Génica , Mutación , Orexinas/genética , Regiones Promotoras Genéticas , Sueño/fisiología , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Orexinas/metabolismo
11.
Eur J Neurosci ; 51(1): 422-428, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-30144347

RESUMEN

It has been known for many years that genetic influences account for some of the individual differences in human sleep parameters, but the underlying molecular mechanisms remain unclear. With major advances of molecular biology and the recognition of heritable sleep behaviors in humans over the past 30 years, a number of genetic variants have been identified to be associated with human sleep timing, duration and quality, both in healthy individuals and under pathological conditions. Some of these variants were further validated and characterized in animal models, shedding light on the mechanism of how these variants likely alter sleep in humans, which may provide new insights into developing more effective treatments to improve human sleep.


Asunto(s)
Trastornos del Sueño-Vigilia , Sueño , Animales , Ritmo Circadiano , Humanos , Individualidad , Modelos Animales , Biología Molecular , Sueño/genética
12.
Proc Natl Acad Sci U S A ; 113(11): E1536-44, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26903630

RESUMEN

In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes.


Asunto(s)
Afecto/fisiología , Proteínas Circadianas Period/genética , Trastorno Afectivo Estacional/genética , Anciano , Secuencia de Aminoácidos , Animales , Relojes Circadianos/genética , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteínas Circadianas Period/metabolismo , Fotoperiodo , Estabilidad Proteica , Trastornos del Sueño del Ritmo Circadiano/genética
13.
Annu Rev Physiol ; 77: 525-41, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25340963

RESUMEN

As noted in the separate introduction to this special topic section, episodic and electrical disorders can appear quite different clinically and yet share many overlapping features, including attack precipitants, therapeutic responses, natural history, and the types of genes that cause many of the genetic forms (i.e., ion channel genes). Thus, as we mapped and attempted to clone genes causing other episodic disorders, ion channels were always outstanding candidates when they mapped to the critical region of linkage in such a family. However, some of these disorders do not result from mutations in channels. This realization has opened up large and exciting new areas for the pathogenesis of these disorders. In some cases, the mutations occur in genes of unknown function or without understanding of molecular pathogenesis. Recently, emerging insights into a fascinating group of episodic movement disorders, the paroxysmal dyskinesias, and study of the causative genes and proteins are leading to the emerging concept of episodic electric disorders resulting from synaptic dysfunction. Much work remains to be done, but the field is evolving rapidly. As it does, we have come to realize that the molecular pathogenesis of electrical and episodic disorders is more complex than a scenario in which such disorders are simply due to mutations in the primary determinants of membrane excitability (channels).


Asunto(s)
Mutación/genética , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/fisiopatología , Sinapsis/genética , Sinapsis/fisiología , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/fisiología , Quinasa Idelta de la Caseína/genética , Quinasa Idelta de la Caseína/fisiología , Modelos Animales de Enfermedad , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/fisiología , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/fisiología , Ratones , Proteínas Musculares/genética , Proteínas Musculares/fisiología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiología
14.
Proc Natl Acad Sci U S A ; 112(10): 2935-41, 2015 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-25730884

RESUMEN

Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder precipitated by coffee, alcohol, and stress. We previously identified the causative gene but the function of the encoded protein remains unknown. We also generated a PNKD mouse model that revealed dysregulated dopamine signaling in vivo. Here, we show that PNKD interacts with synaptic active zone proteins Rab3-interacting molecule (RIM)1 and RIM2, localizes to synapses, and modulates neurotransmitter release. Overexpressed PNKD protein suppresses release, and mutant PNKD protein is less effective than wild-type at inhibiting exocytosis. In PNKD KO mice, RIM1/2 protein levels are reduced and synaptic strength is impaired. Thus, PNKD is a novel synaptic protein with a regulatory role in neurotransmitter release.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Corea/metabolismo , Exocitosis/fisiología , Proteínas Musculares/fisiología , Vesículas Sinápticas/metabolismo , Animales , Ratones , Ratones Noqueados , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Unión Proteica
15.
Proc Natl Acad Sci U S A ; 110(47): 19101-6, 2013 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-24191038

RESUMEN

VLGR1 (very large G protein-coupled receptor 1), also known as MASS1 (monogenic audiogenic seizure susceptible 1), is an orphan G protein-coupled receptor that contains a large extracellular N terminus with 35 calcium-binding domains. A truncating mutation in the Mass1 gene causes autosomal recessive, sound-induced seizures in the Frings mouse. However, the function of MASS1 and the mechanism underlying Frings mouse epilepsy are not known. Here, we found that MASS1 protein is enriched in the myelinated regions of the superior and inferior colliculi, critical areas for the initiation and propagation of audiogenic seizures. Using a panel of myelin antibodies, we discovered that myelin-associated glycoprotein (MAG) expression is dramatically decreased in Frings mice. MASS1 inhibits the ubiquitylation of MAG, thus enhancing the stability of this protein, and the calcium-binding domains of MASS1 are essential for this regulation. Furthermore, MASS1 interacts with Gαs/Gαq and activates PKA and PKC in response to extracellular calcium. Suppression of signaling by MASS1 RNAi or a specific inhibitor abrogates MAG up-regulation. We postulate that MASS1 senses extracellular calcium and activates cytosolic PKA/PKC pathways to regulate myelination by means of MAG protein stability in myelin-forming cells of the auditory pathway. Further work is required to determine whether MAG dysregulation is a cause or consequence of audiogenic epilepsy and whether there are other pathways regulated by MASS1.


Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Epilepsia Refleja/genética , Modelos Biológicos , Glicoproteína Asociada a Mielina/metabolismo , Proteína Quinasa C/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/fisiología , Animales , Calcio/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Epilepsia Refleja/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Inmunohistoquímica , Ratones , Microscopía Electrónica de Transmisión , Ubiquitinación
16.
Proc Natl Acad Sci U S A ; 110(43): 17468-73, 2013 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-24101522

RESUMEN

Demyelinating disorders including leukodystrophies are devastating conditions that are still in need of better understanding, and both oligodendrocyte differentiation and myelin synthesis pathways are potential avenues for developing treatment. Overexpression of lamin B1 leads to leukodystrophy characterized by demyelination of the central nervous system, and microRNA-23 (miR-23) was found to suppress lamin B1 and enhance oligodendrocyte differentiation in vitro. Here, we demonstrated that miR-23a-overexpressing mice have increased myelin thickness, providing in vivo evidence that miR-23a enhances both oligodendrocyte differentiation and myelin synthesis. Using this mouse model, we explored possible miR-23a targets and revealed that the phosphatase and tensin homologue/phosphatidylinositol trisphosphate kinase/Akt/mammalian target of rapamycin pathway is modulated by miR-23a. Additionally, a long noncoding RNA, 2700046G09Rik, was identified as a miR-23a target and modulates phosphatase and tensin homologue itself in a miR-23a-dependent manner. The data presented here imply a unique role for miR-23a in the coordination of proteins and noncoding RNAs in generating and maintaining healthy myelin.


Asunto(s)
Diferenciación Celular/genética , Sistema Nervioso Central/metabolismo , MicroARNs/genética , Vaina de Mielina/genética , Oligodendroglía/metabolismo , Animales , Western Blotting , Diferenciación Celular/fisiología , Células Cultivadas , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/metabolismo , Microscopía Electrónica , Vaina de Mielina/fisiología , Vaina de Mielina/ultraestructura , Oligodendroglía/citología , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Transcriptoma
17.
Crit Rev Biochem Mol Biol ; 48(5): 465-75, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24001255

RESUMEN

Sleep behavior remains one of the most enigmatic areas of life. The unanswered questions range from "why do we sleep?" to "how we can improve sleep in today's society?" Identification of mutations responsible for altered circadian regulation of human sleep lead to unique opportunities for probing these territories. In this review, we summarize causative circadian mutations found from familial genetic studies to date. We also describe how these mutations mechanistically affect circadian function and lead to altered sleep behaviors, including shifted or shortening of sleep patterns. In addition, we discuss how the investigation of mutations can not only expand our understanding of the molecular mechanisms regulating the circadian clock and sleep duration, but also bridge the pathways between clock/sleep and other human physiological conditions and ailments such as metabolic regulation and migraine headaches.


Asunto(s)
Ritmo Circadiano/genética , Mutación/genética , Sueño/genética , Animales , Relojes Biológicos/genética , Humanos , Fenotipo , Procesamiento Proteico-Postraduccional
18.
Trends Genet ; 28(12): 598-605, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22939700

RESUMEN

The study of circadian rhythms is emerging as a fruitful opportunity for understanding cellular mechanisms that govern human physiology and behavior, fueled by evidence directly linking sleep disorders to genetic mutations affecting circadian molecular pathways. Familial advanced sleep-phase disorder (FASPD) is the first recognized Mendelian circadian rhythm trait, and affected individuals exhibit exceptionally early sleep-wake onset due to altered post-translational regulation of period homolog 2 (PER2). Behavioral and cellular circadian rhythms are analogously affected because the circadian period length of behavior is reduced in the absence of environmental time cues, and cycle duration of the molecular clock is likewise shortened. In light of these findings, we review the PER2 dynamics in the context of circadian regulation to reveal the mechanism of sleep-schedule modulation. Understanding PER2 regulation and functionality may shed new light on how our genetic composition can influence our sleep-wake behaviors.


Asunto(s)
Epigénesis Genética , Proteínas Circadianas Period/metabolismo , Trastornos del Sueño del Ritmo Circadiano/genética , Animales , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulación de la Expresión Génica , Humanos , Mutación , Proteínas Circadianas Period/genética , Fosforilación , Procesamiento Proteico-Postraduccional , Transporte de Proteínas , Vigilia/genética
19.
Proc Natl Acad Sci U S A ; 109(50): 20679-84, 2012 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-23185022

RESUMEN

Temporally restricted feeding (RF) can phase reset the circadian clocks in numerous tissues in mammals, contributing to altered timing of behavioral and physiological rhythms. However, little is known regarding the underlying molecular mechanism. Here we demonstrate a role for the gamma isotype of protein kinase C (PKCγ) in food-mediated entrainment of behavior and the molecular clock. We found that daytime RF reduced late-night activity in wild-type mice but not mice homozygous for a null mutation of PKCγ (PKCγ(-/-)). Molecular analysis revealed that PKCγ exhibited RF-induced changes in activation patterns in the cerebral cortex and that RF failed to substantially phase shift the oscillation of clock gene transcripts in the absence of PKCγ. PKCγ exerts effects on the clock, at least in part, by stabilizing the core clock component brain and muscle aryl hydrocarbon receptor nuclear translocator like 1 (BMAL1) and reducing its ubiquitylation in a deubiquitination-dependent manner. Taken together, these results suggest that PKCγ plays a role in food entrainment by regulating BMAL1 stability.


Asunto(s)
Factores de Transcripción ARNTL/fisiología , Ritmo Circadiano/fisiología , Conducta Alimentaria/fisiología , Proteína Quinasa C/fisiología , Factores de Transcripción ARNTL/genética , Animales , Corteza Cerebral/fisiología , Ritmo Circadiano/genética , Ingestión de Alimentos/genética , Ingestión de Alimentos/fisiología , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Neurológicos , Mutación , Fotoperiodo , Proteína Quinasa C/deficiencia , Proteína Quinasa C/genética , Estabilidad Proteica , Transducción de Señal , Ubiquitinación
20.
Nat Genet ; 38(10): 1114-23, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16951681

RESUMEN

Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by symmetrical widespread myelin loss in the central nervous system, with a phenotype similar to chronic progressive multiple sclerosis. In this study, we identify a genomic duplication that causes ADLD. Affected individuals carry an extra copy of the gene for the nuclear laminar protein lamin B1, resulting in increased gene dosage in brain tissue from individuals with ADLD. Increased expression of lamin B1 in Drosophila melanogaster resulted in a degenerative phenotype. In addition, an abnormal nuclear morphology was apparent when cultured cells overexpressed this protein. This is the first human disease attributable to mutations in the gene encoding lamin B1. Antibodies to lamin B are found in individuals with autoimmune diseases, and it is also an antigen recognized by a monoclonal antibody raised against plaques from brains of individuals with multiple sclerosis. This raises the possibility that lamin B may be a link to the autoimmune attack that occurs in multiple sclerosis.


Asunto(s)
Duplicación de Gen , Genes Dominantes , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Lamina Tipo B/genética , Animales , Secuencia de Bases , Encéfalo/patología , Encéfalo/fisiología , Células Cultivadas , Análisis Mutacional de ADN , Drosophila melanogaster/genética , Femenino , Dosificación de Gen , Ligamiento Genético , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/patología , Humanos , Masculino , Datos de Secuencia Molecular
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