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1.
Cell ; 186(24): 5394-5410.e18, 2023 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-37922901

RESUMEN

Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Its symptoms are typically treated with levodopa or dopamine receptor agonists, but its action lacks specificity due to the wide distribution of dopamine receptors in the central nervous system and periphery. Here, we report the development of a gene therapy strategy to selectively manipulate PD-affected circuitry. Targeting striatal D1 medium spiny neurons (MSNs), whose activity is chronically suppressed in PD, we engineered a therapeutic strategy comprised of a highly efficient retrograde adeno-associated virus (AAV), promoter elements with strong D1-MSN activity, and a chemogenetic effector to enable precise D1-MSN activation after systemic ligand administration. Application of this therapeutic approach rescues locomotion, tremor, and motor skill defects in both mouse and primate models of PD, supporting the feasibility of targeted circuit modulation tools for the treatment of PD in humans.


Asunto(s)
Terapia Genética , Enfermedad de Parkinson , Animales , Humanos , Ratones , Cuerpo Estriado/metabolismo , Levodopa/uso terapéutico , Levodopa/genética , Neuronas/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Primates , Receptores de Dopamina D1/metabolismo , Modelos Animales de Enfermedad
2.
BMC Plant Biol ; 24(1): 424, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38764045

RESUMEN

Rutaceae family comprises economically important plants due to their extensive applications in spices, food, oil, medicine, etc. The Rutaceae plants is able to better utilization through biotechnology. Modern biotechnological approaches primarily rely on the heterologous expression of functional proteins in different vectors. However, several proteins are difficult to express outside their native environment. The expression potential of functional genes in heterologous systems can be maximized by replacing the rare synonymous codons in the vector with preferred optimal codons of functional genes. Codon usage bias plays a critical role in biogenetic engineering-based research and development. In the current study, 727 coding sequences (CDSs) obtained from the chloroplast genomes of ten Rutaceae plant family members were analyzed for codon usage bias. The nucleotide composition analysis of codons showed that these codons were rich in A/T(U) bases and preferred A/T(U) endings. Analyses of neutrality plots, effective number of codons (ENC) plots, and correlations between ENC and codon adaptation index (CAI) were conducted, which revealed that natural selection is a major driving force for the Rutaceae plant family's codon usage bias, followed by base mutation. In the ENC vs. CAI plot, codon usage bias in the Rutaceae family had a negligible relationship with gene expression level. For each sample, we screened 12 codons as preferred and high-frequency codons simultaneously, of which GCU encoding Ala, UUA encoding Leu, and AGA encoding Arg were the most preferred codons. Taken together, our study unraveled the synonymous codon usage pattern in the Rutaceae family, providing valuable information for the genetic engineering of Rutaceae plant species in the future.


Asunto(s)
Uso de Codones , Genoma del Cloroplasto , Plantas Medicinales , Rutaceae , Plantas Medicinales/genética , Rutaceae/genética , Codón/genética
3.
Innovation (Camb) ; 4(1): 100358, 2023 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-36583100

RESUMEN

Maintaining body temperature within a narrow range is vital for warm-blooded animals. In rodents, the preoptic area (POA) of the hypothalamus detects and regulates core body temperature. However, knowledge about the thermal regulation center in primates remains limited. Here, we show that activating a subpopulation of POA neurons by a chemogenetic strategy reliably induces hypothermia in anesthetized and freely moving macaques. Comprehensive monitoring of physiological parameters reveals that such hypothermia is accompanied by autonomic changes including a rise in heart rate, skeletal muscle activity, and correlated biomarkers in blood. Consistent with enhanced ambulatory movement during hypothermia, the animals show a full range of cold-defense behaviors. Resting-state fMRI confirms the chemogenetic activation of POA and charts a brain-wide network of thermoregulation. Altogether, our findings demonstrate the central regulation of body temperature in primates and pave the way for future application in clinical practice.

4.
Cell Rep ; 42(11): 113348, 2023 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-37910509

RESUMEN

Promoters are essential tools for basic and translational neuroscience research. An ideal promoter should possess the shortest possible DNA sequence with cell-type selectivity. However, whether ultra-compact promoters can offer neuron-specific expression is unclear. Here, we report the development of an extremely short promoter that enables selective gene expression in neurons, but not glial cells, in the brain. The promoter sequence originates from the human CALM1 gene and is only 120 bp in size. The CALM1 promoter (pCALM1) embedded in an adeno-associated virus (AAV) genome directed broad reporter expression in excitatory and inhibitory neurons in mouse and monkey brains. Moreover, pCALM1, when inserted into an all-in-one AAV vector expressing SpCas9 and sgRNA, drives constitutive and conditional in vivo gene editing in neurons and elicits functional alterations. These data demonstrate the ability of pCALM1 to conduct restricted neuronal gene expression, illustrating the feasibility of ultra-miniature promoters for targeting brain-cell subtypes.


Asunto(s)
Neuronas , ARN Guía de Sistemas CRISPR-Cas , Ratones , Animales , Humanos , Neuronas/metabolismo , Encéfalo/metabolismo , Neuroglía/metabolismo , Terapia Genética , Vectores Genéticos/genética , Dependovirus/genética , Dependovirus/metabolismo
5.
Mol Plant ; 14(7): 1135-1148, 2021 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-33845208

RESUMEN

Heading date is a critical trait that determines the regional adaptability and grain productivity of many crops. Although rice is a facultative short-day plant, its domestication led to the Ghd7-Ehd1-Hd3a/RFT1 pathway for adaptation to long-day conditions (LDs). The formation of the "florigen activation complex" (FAC) containing florigen Hd3a has been characterized. However, the molecular composition of the FAC that contains RFT1 for long-day flowering is unclear. We show here that RFT1 forms a ternary FAC with 14-3-3 proteins and OsFD1 to promote flowering under LDs. We identified a calcineurin B-like-interacting protein kinase, OsCIPK3, which directly interacts with and phosphorylates OsFD1, thereby facilitating the localization of the FAC to the nucleus. Mutation in OsCIPK3 results in a late heading date under LDs but a normal heading date under short-day conditions. Collectively, our results suggest that OsCIPK3 phosphorylates OsFD1 to promote RFT1-containing FAC formation and consequently induce flowering in rice under LDs.


Asunto(s)
Florigena/metabolismo , Flores/crecimiento & desarrollo , Complejos Multiproteicos/metabolismo , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Flores/metabolismo , Proteínas Asociadas a Matriz Nuclear/metabolismo , Oryza/genética , Fosforilación , Fotoperiodo , Proteínas de Plantas/genética
6.
Hortic Res ; 8(1): 205, 2021 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-34480029

RESUMEN

Zanthoxylum bungeanum is an important spice and medicinal plant that is unique for its accumulation of abundant secondary metabolites, which create a characteristic aroma and tingling sensation in the mouth. Owing to the high proportion of repetitive sequences, high heterozygosity, and increased chromosome number of Z. bungeanum, the assembly of its chromosomal pseudomolecules is extremely challenging. Here, we present a genome sequence for Z. bungeanum, with a dramatically expanded size of 4.23 Gb, assembled into 68 chromosomes. This genome is approximately tenfold larger than that of its close relative Citrus sinensis. After the divergence of Zanthoxylum and Citrus, the lineage-specific whole-genome duplication event η-WGD approximately 26.8 million years ago (MYA) and the recent transposable element (TE) burst ~6.41 MYA account for the substantial genome expansion in Z. bungeanum. The independent Zanthoxylum-specific WGD event was followed by numerous fusion/fission events that shaped the genomic architecture. Integrative genomic and transcriptomic analyses suggested that prominent species-specific gene family expansions and changes in gene expression have shaped the biosynthesis of sanshools, terpenoids, and anthocyanins, which contribute to the special flavor and appearance of Z. bungeanum. In summary, the reference genome provides a valuable model for studying the impact of WGDs with recent TE activity on gene gain and loss and genome reconstruction and provides resources to accelerate Zanthoxylum improvement.

7.
Hortic Res ; 7: 158, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33082965

RESUMEN

Chinese pepper, mainly including Zanthoxylum bungeanum and Zanthoxylum armatum, is an economically important crop popular in Asian countries due to its unique taste characteristics and potential medical uses. Numerous cultivars of Chinese pepper have been developed in China through long-term domestication. To better understand the population structure, demographic history, and speciation of Chinese pepper, we performed a comprehensive analysis at a genome-wide level by analyzing 38,395 genomic SNPs that were identified in 112 cultivated and wild accessions using a high-throughput genome-wide genotyping-by-sequencing (GBS) approach. Our analysis provides genetic evidence of multiple splitting events occurring between and within species, resulting in at least four clades in Z. bungeanum and two clades in Z. armatum. Despite no evidence of recent admixture between species, we detected substantial gene flow within species. Estimates of demographic dynamics and species distribution modeling suggest that climatic oscillations during the Pleistocene (including the Penultimate Glaciation and the Last Glacial Maximum) and recent domestication events together shaped the demography and evolution of Chinese pepper. Our analyses also suggest that southeastern Gansu province is the most likely origin of Z. bungeanum in China. These findings provide comprehensive insights into genetic diversity, population structure, demography, and adaptation in Zanthoxylum.

8.
Nat Neurosci ; 23(4): 520-532, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32123378

RESUMEN

Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B-/- mouse model of ASD. Male and female Shank3B-/- mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.


Asunto(s)
Potenciales de Acción/fisiología , Trastorno del Espectro Autista/fisiopatología , Neuronas GABAérgicas/fisiología , Proteínas del Tejido Nervioso/genética , Corteza Somatosensorial/fisiopatología , Percepción del Tacto/fisiología , Animales , Trastorno del Espectro Autista/genética , Modelos Animales de Enfermedad , Ratones , Proteínas de Microfilamentos , Estimulación Física , Células Piramidales/fisiología , Umbral Sensorial/fisiología , Tacto/fisiología
9.
Appl Plant Sci ; 6(6): e01157, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30131899

RESUMEN

PREMISE OF THE STUDY: The genus Zanthoxylum in the Rutaceae family of trees and shrubs has a long history of domestication and cultivation in Asia for both economic and medicinal purposes. However, many Zanthoxylum species are morphologically similar and are easily confused. This often leads to false authentication of source materials and confusion in herbal markets, hindering their safe utilization and genetic resource conservation. DNA barcoding is a promising tool for identifying plant taxa. METHODS: We used three candidate DNA barcoding regions (ITS2, ETS, and trnH-psbA) to identify 69 accessions representing 13 Chinese Zanthoxylum species. The discriminatory capabilities of these regions were evaluated in terms of PCR amplification success, intra- and interspecific divergence, DNA barcoding gaps, and identification efficiency using the BLAST and tree-building methods. RESULTS: ITS2 proved the most useful for discriminating Chinese Zanthoxylum species, with a correct identification rate of 100%, and this region also exhibited significantly higher intra- and interspecific divergence. DISCUSSION: Phylogenetic analysis confirmed that ITS2 has a powerful discriminatory ability both at and below the species level. We confirmed that ITS2 is a powerful barcoding region for identifying Chinese Zanthoxylum species, and will be useful for analyzing and managing Chinese Zanthoxylum germplasm collections.

10.
Sci Rep ; 7(1): 16754, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29196697

RESUMEN

Zanthoxylum, an ancient economic crop in Asia, has a satisfying aromatic taste and immense medicinal values. A lack of genomic information and genetic markers has limited the evolutionary analysis and genetic improvement of Zanthoxylum species and their close relatives. To better understand the evolution, domestication, and divergence of Zanthoxylum, we present a de novo transcriptome analysis of an elite cultivar of Z. bungeanum using Illumina sequencing; we then developed simple sequence repeat markers for identification of Zanthoxylum. In total, we predicted 45,057 unigenes and 22,212 protein coding sequences, approximately 90% of which showed significant similarities to known proteins in databases. Phylogenetic analysis indicated that Zanthoxylum is relatively recent and estimated to have diverged from Citrus ca. 36.5-37.7 million years ago. We also detected a whole-genome duplication event in Zanthoxylum that occurred 14 million years ago. We found no protein coding sequences that were significantly under positive selection by Ka/Ks. Simple sequence repeat analysis divided 31 Zanthoxylum cultivars and landraces into three major groups. This Zanthoxylum reference transcriptome provides crucial information for the evolutionary study of the Zanthoxylum genus and the Rutaceae family, and facilitates the establishment of more effective Zanthoxylum breeding programs.


Asunto(s)
Evolución Molecular , Perfilación de la Expresión Génica , Repeticiones de Microsatélite , Transcriptoma , Zanthoxylum/genética , Biología Computacional/métodos , Ontología de Genes , Marcadores Genéticos , Secuenciación de Nucleótidos de Alto Rendimiento , Anotación de Secuencia Molecular , Sistemas de Lectura Abierta , Filogenia , Polimorfismo de Nucleótido Simple , Zanthoxylum/clasificación
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