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1.
Brain ; 146(3): 954-967, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35411378

RESUMO

Nodding syndrome is an enigmatic recurrent epidemic neurologic disease that affects children in East Africa. The illness begins with vertical nodding of the head and can progress to grand mal seizures and death after several years. The most recent outbreak of nodding syndrome occurred in northern Uganda. We now describe the clinicopathologic spectrum of nodding syndrome in northern Uganda. The neuropathologic findings of 16 children or young adults with fatal nodding syndrome were correlated with the onset, duration and progression of their neurological illness. The affected individuals ranged in age from 14 to 25 years at the time of death with a duration of illness ranging from 6-15 years. All 16 cases had chronic seizures. In 10 cases, detailed clinical histories were available and showed that three individuals had a clinical course that was predominantly characterized by epilepsy, whereas the other seven individuals had progressive cognitive, behavioural and motor decline, in addition to epilepsy. The main neuropathologic findings included: tau pathology (16/16 cases), cerebellar degeneration (11/16 cases) and white matter degeneration (7/16 cases). The tau pathology was characterized by filamentous tau-positive deposits in the form of neurofibrillary tangles, pre-tangles and dot-like grains and threads in the neuropil. All cases showed some degree of tau pathology in the neocortex and in the locus coeruleus with frequent involvement of the substantia nigra and tegmental nuclei and lesser involvement of other grey matter sites, but there was a lack of glial tau pathology. The tau pathology in the neocortex showed a multifocal superficial laminar pattern. We conclude that nodding syndrome is a clinicopathological entity associated consistently with tau pathology, but our observations did not establish the cause of the disease, or an explanation for the tau pathology.


Assuntos
Epilepsia , Síndrome do Cabeceio , Criança , Adulto Jovem , Humanos , Adolescente , Adulto , Uganda/epidemiologia , Síndrome do Cabeceio/epidemiologia , Síndrome do Cabeceio/complicações , Síndrome do Cabeceio/patologia , Epilepsia/patologia , Emaranhados Neurofibrilares/patologia , Convulsões/complicações
2.
Brain ; 144(11): 3461-3476, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34115105

RESUMO

TDP-43 nuclear depletion and concurrent cytoplasmic accumulation in vulnerable neurons is a hallmark feature of progressive neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cellular stress signalling and stress granule dynamics are now recognized to play a role in ALS/FTD pathogenesis. Defective stress granule assembly is associated with increased cellular vulnerability and death. Ras-GAP SH3-domain-binding protein 1 (G3BP1) is a critical stress granule assembly factor. Here, we define that TDP-43 stabilizes G3BP1 transcripts via direct binding of a highly conserved cis regulatory element within the 3' untranslated region. Moreover, we show in vitro and in vivo that nuclear TDP-43 depletion is sufficient to reduce G3BP1 protein levels. Finally, we establish that G3BP1 transcripts are reduced in ALS/FTD patient neurons bearing TDP-43 cytoplasmic inclusions/nuclear depletion. Thus, our data indicate that, in ALS/FTD, there is a compromised stress granule response in disease-affected neurons due to impaired G3BP1 mRNA stability caused by TDP-43 nuclear depletion. These data implicate TDP-43 and G3BP1 loss of function as contributors to disease.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Demência Frontotemporal/metabolismo , Neurônios/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Esclerose Lateral Amiotrófica/patologia , Células Cultivadas , Demência Frontotemporal/patologia , Humanos , Neurônios/patologia , RNA Mensageiro
3.
Brain ; 141(10): 2895-2907, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30252044

RESUMO

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.


Assuntos
Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , Demência Frontotemporal/genética , Regulação da Expressão Gênica/genética , Idade de Início , Idoso , Ilhas de CpG , Metilação de DNA , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
4.
Am J Hum Genet ; 96(6): 962-70, 2015 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-26004200

RESUMO

An expanded G4C2 repeat in C9orf72 represents the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have occurred only once in human history and subsequently spread throughout the population. However, our present findings support a hypothesis of multiple origins for the expansion. We report a British-Canadian family in whom a ∼70-repeat allele from the father (unaffected by ALS or FTLD at age 89 years) expanded during parent-offspring transmission and started the first generation affected by ALS (four children carry an ∼1,750-repeat allele). Epigenetic and RNA-expression analyses further discriminated the offspring's large expansions (which were methylated and associated with reduced C9orf72 expression) from the ∼70-repeat allele (which was unmethylated and associated with upregulation of C9orf72). Moreover, RNA foci were only detected in fibroblasts from offspring with large expansions, but not in the father, who has the ∼70-repeat allele. All family members with expansions were found to have an ancient known risk haplotype, although it was inherited on a unique 5-Mb genetic backbone. We conclude that small expansions (e.g., 70 repeats) might be considered "pre-mutations" to reflect their propensity to expand in the next generation. Follow-up studies might help explain the high frequency of ALS- or FTLD-affected individuals with an expansion but without a familial history (e.g., 21% among Finnish ALS subjects).


Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Expansão das Repetições de DNA/genética , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Proteínas/genética , Southern Blotting , Proteína C9orf72 , Canadá , Metilação de DNA/genética , Haplótipos/genética , Humanos , Linhagem , Reação em Cadeia da Polimerase
5.
Acta Neuropathol ; 136(5): 691-697, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30219940

RESUMO

Nodding syndrome is an epidemic neurologic disorder of unknown cause that affects children in the subsistence-farming communities of East Africa. We report the neuropathologic findings in five fatal cases (13-18 years of age at death) of nodding syndrome from the Acholi people in northern Uganda. Neuropathologic examination revealed tau-immunoreactive neuronal neurofibrillary tangles, pre-tangles, neuropil threads, and dot-like lesions involving the cerebral cortex, subcortical nuclei and brainstem. There was preferential involvement of the frontal and temporal lobes in a patchy distribution, mostly involving the crests of gyri and the superficial cortical lamina. The mesencephalopontine tegmental nuclei, substantia nigra, and locus coeruleus revealed globose neurofibrillary tangles and threads. We conclude that nodding syndrome is a tauopathy and may represent a newly recognized neurodegenerative disease.


Assuntos
Encéfalo/patologia , Emaranhados Neurofibrilares/patologia , Síndrome do Cabeceio/patologia , Síndrome do Cabeceio/fisiopatologia , Tauopatias/fisiopatologia , Adolescente , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Síndrome do Cabeceio/epidemiologia , Tauopatias/epidemiologia , Uganda/epidemiologia
6.
Ann Neurol ; 78(4): 568-83, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26174152

RESUMO

OBJECTIVE: A noncoding hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). It has been reported that the repeat expansion causes a downregulation of C9orf72 transcripts, suggesting that haploinsufficiency may contribute to disease pathogenesis. Two protein isoforms are generated from three alternatively spliced transcripts of C9orf72; a long form (C9-L) and a short form (C9-S), and their function(s) are largely unknown owing to lack of specific antibodies. METHODS: To investigate C9orf72 protein properties, we developed novel antibodies that recognize either C9-L or C9-S. Multiple techniques, including Western blot, immunohistochemistry, and coimmunoprecipitation, were used to determine the expression levels and subcellular localizations of C9-L and C9-S. RESULTS: Investigation of expression of C9-L and C9-S demonstrated distinct biochemical profiles, region-specific changes, and distinct subcellular localizations in ALS tissues. In particular, C9-L antibody exhibited a diffuse cytoplasmic staining in neurons and labeled large speckles in cerebellar Purkinje cells. In contrast, C9-S antibody gave very specific labeling of the nuclear membrane in healthy neurons, with apparent relocalization to the plasma membrane of diseased motor neurons in ALS. Coimmunoprecipitation experiments revealed an interaction of the C9-isoforms with both Importin ß1 and Ran-GTPase, components of the nuclear pore complex. INTERPRETATION: Using these antibodies, we have shown that C9orf72 may be involved in nucleocytoplasmic shuttling and this may have relevance to pathophysiology of ALS/FTLD. Our antibodies have provided improved detection of C9orf72 protein isoforms, which will help elucidate its physiological function and role in ALS/FTLD.


Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Anticorpos/análise , Proteínas/análise , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Esclerose Lateral Amiotrófica/metabolismo , Anticorpos/metabolismo , Proteína C9orf72 , Cerebelo/química , Cerebelo/metabolismo , Cerebelo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Neurônios Motores/química , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Isoformas de Proteínas/análise , Isoformas de Proteínas/biossíntese , Proteínas/metabolismo
8.
bioRxiv ; 2023 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-38187588

RESUMO

The understanding of how different cell types contribute to amyotrophic lateral sclerosis (ALS) pathogenesis is limited. Here we generated a single-nucleus transcriptomic and epigenomic atlas of the frontal cortex of ALS cases with C9orf72 (C9) hexanucleotide repeat expansions and sporadic ALS (sALS). Our findings reveal shared pathways in C9-ALS and sALS, characterized by synaptic dysfunction in excitatory neurons and a disease-associated state in microglia. The disease subtypes diverge with loss of astrocyte homeostasis in C9-ALS, and a more substantial disturbance of inhibitory neurons in sALS. Leveraging high depth 3'-end sequencing, we found a widespread switch towards distal polyadenylation (PA) site usage across ALS subtypes relative to controls. To explore this differential alternative PA (APA), we developed APA-Net, a deep neural network model that uses transcript sequence and expression levels of RNA-binding proteins (RBPs) to predict cell-type specific APA usage and RBP interactions likely to regulate APA across disease subtypes.

9.
Acta Neuropathol Commun ; 7(1): 161, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31651360

RESUMO

A hexanucleotide repeat expansion in a noncoding region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Reduction of select or total C9orf72 transcript and protein levels is observed in postmortem C9-ALS/FTD tissue, and loss of C9orf72 orthologues in zebrafish and C. elegans results in motor deficits. However, how the reduction in C9orf72 in ALS and FTD might contribute to the disease process remains poorly understood. It has been shown that C9orf72 interacts and forms a complex with SMCR8 and WDR41, acting as a guanine exchange factor for Rab GTPases. Given the known synaptosomal compartmentalization of C9orf72-interacting Rab GTPases, we hypothesized that C9orf72 localization to synaptosomes would be required for the regulation of Rab GTPases and receptor trafficking. This study combined synaptosomal and post-synaptic density preparations together with a knockout-confirmed monoclonal antibody for C9orf72 to assess the localization and role of C9orf72 in the synaptosomes of mouse forebrains. Here, we found C9orf72 to be localized to both the pre- and post-synaptic compartment, as confirmed by both post-synaptic immunoprecipitation and immunofluorescence labelling. In C9orf72 knockout (C9-KO) mice, we demonstrated that pre-synaptic Rab3a, Rab5, and Rab11 protein levels remained stable compared with wild-type littermates (C9-WT). Strikingly, post-synaptic preparations from C9-KO mouse forebrains demonstrated a complete loss of Smcr8 protein levels, together with a significant downregulation of Rab39b and a concomitant upregulation of GluR1 compared with C9-WT mice. We confirmed the localization of Rab39b downregulation and GluR1 upregulation to the dorsal hippocampus of C9-KO mice by immunofluorescence. These results indicate that C9orf72 is essential for the regulation of post-synaptic receptor levels, and implicates loss of C9orf72 in contributing to synaptic dysfunction and related excitotoxicity in ALS and FTD.


Assuntos
Proteína C9orf72/metabolismo , Densidade Pós-Sináptica/metabolismo , Prosencéfalo/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Proteína C9orf72/genética , Hipocampo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transporte Proteico
10.
Elife ; 82019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31612854

RESUMO

Antibodies are a key resource in biomedical research yet there are no community-accepted standards to rigorously characterize their quality. Here we develop a procedure to validate pre-existing antibodies. Human cell lines with high expression of a target, determined through a proteomics database, are modified with CRISPR/Cas9 to knockout (KO) the corresponding gene. Commercial antibodies against the target are purchased and tested by immunoblot comparing parental and KO. Validated antibodies are used to definitively identify the most highly expressing cell lines, new KOs are generated if needed, and the lines are screened by immunoprecipitation and immunofluorescence. Selected antibodies are used for more intensive procedures such as immunohistochemistry. The pipeline is easy to implement and scalable. Application to the major ALS disease gene C9ORF72 identified high-quality antibodies revealing C9ORF72 localization to phagosomes/lysosomes. Antibodies that do not recognize C9ORF72 have been used in highly cited papers, raising concern over previously reported C9ORF72 properties.


Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Anticorpos Monoclonais/química , Proteína C9orf72/genética , Demência Frontotemporal/diagnóstico , Imuno-Histoquímica/normas , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/metabolismo , Animais , Anticorpos Monoclonais/classificação , Anticorpos Monoclonais/imunologia , Biomarcadores/metabolismo , Proteína C9orf72/imunologia , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Demência Frontotemporal/genética , Demência Frontotemporal/imunologia , Demência Frontotemporal/metabolismo , Edição de Genes , Expressão Gênica , Células HEK293 , Humanos , Lisossomos/genética , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoblastos/metabolismo , Osteoblastos/ultraestrutura , Fagossomos/genética , Fagossomos/metabolismo , Fagossomos/ultraestrutura , Células RAW 264.7
11.
Mol Neurobiol ; 55(12): 8826-8841, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29603092

RESUMO

Clinical diagnosis of Alzheimer's disease (AD) prior to the age of 65 years is classified as young-onset (YOAD), whereas diagnosis after the age of 65 years is considered late-onset (LOAD). Although rare autosomal mutations more commonly associate with YOAD, most YOAD and LOAD cases are sporadic. YOAD and LOAD share amyloid and tau pathology, but many YOAD patients show increased disease severity and rate of progression. The current study examined the microRNA (miRNA) expression profile from exosomes isolated from the cerebrospinal fluid (CSF) of YOAD patients with biomarker-confirmed AD. Results uncovered miR-16-5p, miR-125b-5p, miR-451a, and miR-605-5p as differentially expressed in the CSF-derived exosomes of YOAD patients when compared with healthy controls (HC). In a cohort of LOAD patients, miR-125b-5p, miR-451a, and miR-605-5p were similarly altered in expression, but miR-16-5p showed similar expression to control. Analysis of the mRNA targets of these miRNAs revealed transcripts enriched in biological processes relevant to the post-mortem posterior cingulate cortex transcriptome in YOAD from a previously published microarray study, including those related to neuron projections, synaptic signaling, metabolism, apoptosis, and the immune system. Hence, these miRNAs represent novel targets for uncovering disease mechanisms and for biomarker development in both YOAD and LOAD.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , MicroRNAs/líquido cefalorraquidiano , Idade de Início , Idoso , Estudos de Casos e Controles , Exossomos/metabolismo , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Giro do Cíngulo/metabolismo , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
12.
Neurology ; 90(4): e323-e331, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29282338

RESUMO

OBJECTIVE: Suggested C9orf72 disease mechanisms for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration include C9orf72 haploinsufficiency, G4C2/C4G2 RNA foci, and dipeptide repeat (DPR) proteins translated from the G4C2 expansion; however, the role of small expansions (e.g., 30-90 repeats) is unknown and was investigated here. METHODS: We conducted a molecular and pathology study of a family in which the father (unaffected at age 90) carried a 70-repeat allele in blood DNA that expanded to ≈1,750 repeats in his children, causing ALS. RESULTS: Southern blotting revealed different degrees of mosaicism of small and large expansions in the father's tissues from the CNS. Surprisingly, in each mosaic tissue, C9orf72 mRNA levels were significantly increased compared to an ALS-affected daughter with a large expansion. Increased expression correlated with higher levels of the 70-repeat allele (the upregulation was also evident at the protein level). Remarkably, RNA foci and DPR burdens were similar or even significantly increased (in cerebellum) in the unaffected father compared to the daughter with ALS. However, the father did not display TDP-43 pathology and signs of neurodegeneration. CONCLUSION: The presence of RNA foci and DPR pathology was insufficient for disease manifestation and TDP-43 pathology in the mosaic C9orf72 carrier with upregulated C9orf72 expression. It is important to conduct an investigation of similar cases, which could be found among unaffected parents of sporadic C9orf72 patients (e.g., 21% among Finnish patients with ALS). Caution should be taken when consulting carriers of small expansions because disease manifestation could be dependent on the extent of the somatic instability in disease-relevant tissues.


Assuntos
Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Mosaicismo , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/metabolismo , Metilação de DNA , Expansão das Repetições de DNA , Evolução Fatal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , RNA Mensageiro/metabolismo , Regulação para Cima
13.
Neurobiol Aging ; 57: 104-119, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28628896

RESUMO

Cholinergic neurotransmission is impaired in Alzheimer's disease (AD), and loss of basal forebrain cholinergic neurons is a key component of disease pathogenicity and symptomatology. To explore the molecular basis of this cholinergic dysfunction, we paired translating ribosome affinity purification (TRAP) with RNA sequencing (TRAP-Seq) to identify the actively translating mRNAs in anterior forebrain cholinergic neurons in the TgCRND8 mouse model of AD. Bioinformatic analyses revealed the downregulation of 67 of 71 known cholinergic-related transcripts, consistent with cholinergic neuron dysfunction in TgCRND8 mice, as well as transcripts related to oxidative phosphorylation, neurotrophins, and ribosomal processing. Upregulated transcripts included those related to axon guidance, glutamatergic synapses and kinase activity and included AD-risk genes Sorl1 and Ptk2b. In contrast, the total transcriptome of the anterior forebrain showed upregulation in cytokine signaling, microglia, and immune system pathways, including Trem2, Tyrobp, and Inpp5d. Hence, TRAP-Seq clearly distinguished the differential gene expression alterations occurring in cholinergic neurons of TgCRND8 mice compared with wild-type littermates, providing novel candidate pathways to explore for therapeutic development in AD.


Assuntos
Doença de Alzheimer/genética , Neurônios Colinérgicos , Perfilação da Expressão Gênica/métodos , Expressão Gênica , Biossíntese de Proteínas/genética , Animais , Orientação de Axônios/genética , Neurônios Colinérgicos/patologia , Neurônios Colinérgicos/fisiologia , Modelos Animais de Doenças , Quinase 2 de Adesão Focal/genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Membrana Transportadoras/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia , Fatores de Crescimento Neural/genética , Fosforilação/genética , Prosencéfalo/patologia , RNA Mensageiro/genética , Receptores de LDL/genética , Ribossomos/genética , Transmissão Sináptica , Transcriptoma
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