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1.
EMBO Rep ; 25(4): 1835-1858, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38429578

RESUMO

Cancer cachexia is a tumour-induced wasting syndrome, characterised by extreme loss of skeletal muscle. Defective mitochondria can contribute to muscle wasting; however, the underlying mechanisms remain unclear. Using a Drosophila larval model of cancer cachexia, we observed enlarged and dysfunctional muscle mitochondria. Morphological changes were accompanied by upregulation of beta-oxidation proteins and depletion of muscle glycogen and lipid stores. Muscle lipid stores were also decreased in Colon-26 adenocarcinoma mouse muscle samples, and expression of the beta-oxidation gene CPT1A was negatively associated with muscle quality in cachectic patients. Mechanistically, mitochondrial defects result from reduced muscle insulin signalling, downstream of tumour-secreted insulin growth factor binding protein (IGFBP) homologue ImpL2. Strikingly, muscle-specific inhibition of Forkhead box O (FOXO), mitochondrial fusion, or beta-oxidation in tumour-bearing animals preserved muscle integrity. Finally, dietary supplementation with nicotinamide or lipids, improved muscle health in tumour-bearing animals. Overall, our work demonstrates that muscle FOXO, mitochondria dynamics/beta-oxidation and lipid utilisation are key regulators of muscle wasting in cancer cachexia.


Assuntos
Neoplasias do Colo , Proteínas de Drosophila , Insulinas , Camundongos , Animais , Humanos , Caquexia/etiologia , Caquexia/metabolismo , Drosophila/metabolismo , Dinâmica Mitocondrial , Atrofia Muscular/patologia , Músculo Esquelético/metabolismo , Neoplasias do Colo/metabolismo , Insulinas/metabolismo , Lipídeos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo
2.
EMBO Rep ; 24(12): e57695, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-38014610

RESUMO

In this study, we found that in the adipose tissue of wildtype animals, insulin and TGF-ß signalling converge via a BMP antagonist short gastrulation (sog) to regulate ECM remodelling. In tumour bearing animals, Sog also modulates TGF-ß signalling to regulate ECM accumulation in the fat body. TGF-ß signalling causes ECM retention in the fat body and subsequently depletes muscles of fat body-derived ECM proteins. Activation of insulin signalling, inhibition of TGF-ß signalling, or modulation of ECM levels via SPARC, Rab10 or Collagen IV in the fat body, is able to rescue tissue wasting in the presence of tumour. Together, our study highlights the importance of adipose ECM remodelling in the context of cancer cachexia.


Assuntos
Caquexia , Neoplasias , Animais , Caquexia/etiologia , Caquexia/metabolismo , Drosophila , Insulina , Corpo Adiposo/metabolismo , Tecido Adiposo/metabolismo , Fator de Crescimento Transformador beta , Neoplasias/complicações
3.
Dev Biol ; 438(2): 69-83, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29608877

RESUMO

Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder of childhood. It is primarily characterised by high levels of activity, inattention, and impulsivity, and has strong negative impacts on academic functioning. Children with ADHD show a reduction in volume, and hypoactivity, in a range of brain regions. The underlying mechanisms behind these phenotypes are unknown, however, variants in several genes with known roles in neurodevelopment are associated with ADHD. In this review we discuss how these ADHD associated genes contribute to neurodevelopment, and how variants in these genes could give rise to the neurological phenotypes seen in ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Encéfalo/fisiopatologia , Humanos , Comportamento Impulsivo , Transtornos do Neurodesenvolvimento/genética , Neurônios/fisiologia , Sinapses/genética , Sinapses/fisiologia
4.
Am J Med Genet B Neuropsychiatr Genet ; 177(2): 168-180, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28921840

RESUMO

Converging evidence from candidate gene, genome-wide linkage, and association studies support a role of cadherins in the pathophysiology of five major psychiatric disorders including attention deficit hyperactivity disorder, autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). These molecules are transmembrane proteins which act as cell adhesives by forming adherens junctions (AJs) to bind cells within tissues. Members of the cadherin superfamily are also involved in biological processes such as signal transduction and plasticity that have been implicated in the etiology of major psychiatric conditions. Although there are over 110 genes mapped to the cadherin superfamily, our literature survey showed that evidence of association with psychiatric disorders is strongest for CDH7, CHD11, and CDH13. Gene enrichment analysis showed that those cadherin genes implicated in psychiatric disorders were overrepresented in biological processes such as in cell-cell adhesion (GO:0007156 & GO:0098742) and adherens junction organization (GO:0034332). Further, cadherin genes were also mapped to processes that have been linked to the development of psychiatric disorders such as nervous system development (GO:0007399). To further understand the role of cadherin SNPs implicated in psychiatric disorders, we utilized an in silico computational pipeline to functionally annotate associated variants. This analysis yielded eight variants mapped to PCDH1-13, CDH7, CDH11, and CDH13 that are predicted to be biologically functional. Functional genomic evaluation is now required to understand the molecular mechanism by which these variants might confer susceptibility to psychiatric disorders.


Assuntos
Caderinas/genética , Transtornos Mentais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Polimorfismo de Nucleotídeo Único
5.
STAR Protoc ; 3(1): 101230, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35284841

RESUMO

Drosophila has become a popular model for examining the metabolic wasting syndrome, cachexia, characterized by degradation of muscles and fat. Here we present a protocol for quick and consistent scoring of muscle detachment, fat body lipid droplet size, and extracellular matrix (ECM) quantifications in Drosophila larvae. We detail the procedures for dissecting, staining, and imaging third instar Drosophila larval muscle fillets and fat body, and how to utilize FIJI macros for robust quantification of cachectic phenotypes in these dissected tissues. For complete details on the use and execution of this protocol, please refer to Lodge et al. (2021).


Assuntos
Caquexia , Drosophila , Animais , Caquexia/metabolismo , Corpo Adiposo/metabolismo , Larva/metabolismo , Músculos/metabolismo , Fenótipo
6.
Dev Cell ; 56(18): 2664-2680.e6, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34473940

RESUMO

Cachexia, the wasting syndrome commonly observed in advanced cancer patients, accounts for up to one-third of cancer-related mortalities. We have established a Drosophila larval model of organ wasting whereby epithelial overgrowth in eye-antennal discs leads to wasting of the adipose tissue and muscles. The wasting is associated with fat-body remodeling and muscle detachment and is dependent on tumor-secreted matrix metalloproteinase 1 (Mmp1). Mmp1 can both modulate TGFß signaling in the fat body and disrupt basement membrane (BM)/extracellular matrix (ECM) protein localization in both the fat body and the muscle. Inhibition of TGFß signaling or Mmps in the fat body/muscle using a QF2-QUAS binary expression system rescues muscle wasting in the presence of tumor. Altogether, our study proposes that tumor-derived Mmps are central mediators of organ wasting in cancer cachexia.


Assuntos
Tecido Adiposo/metabolismo , Metaloproteinases da Matriz/metabolismo , Músculo Esquelético/metabolismo , Neoplasias/metabolismo , Animais , Membrana Basal/metabolismo , Drosophila/metabolismo , Matriz Extracelular/metabolismo , Atrofia Muscular/metabolismo
7.
Transl Psychiatry ; 10(1): 385, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33159045

RESUMO

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder of childhood with a strong genetic component. Despite the success of mapping ADHD risk loci, little work has been done to experimentally verify the contribution of these loci to ADHD phenotypes. Meta-analysis of four genome-wide association studies in ADHD suggested CHMP7 as a predisposing gene for ADHD. A DNA variant (rs2294123) mapped to CHMP7 has been shown (via bioinformatic analysis) to have a high likelihood for functionality and correlate with reduced transcript levels. We used CRISPR-Cas9 genome editing to generate a chmp7 zebrafish model for ADHD. chmp7+/- fish showed comparable reductions in mRNA levels to individuals homozygous for the CHMP7 ADHD risk allele. These fish displayed significant hyperactivity over a 24-h period at 6 days post-fertilisation compared to chmp7+/+, but this effect did not persist into juvenile and adulthood stages. In addition, chmp7+/- fish had significantly smaller total brain volumes than chmp7+/+ fish. Finally, the hyperactivity at 6 days post-fertilisation was significantly reduced through the application of methylphenidate, a mainstay pharmacological treatment for ADHD. Overall, this study highlights an important role for CHMP7 in the neurodevelopment of ADHD, and demonstrates the utility of zebrafish for modelling the functional effects of genes conferring risk to ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Complexos Endossomais de Distribuição Requeridos para Transporte , Metilfenidato , Animais , Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo , Criança , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Edição de Genes , Estudo de Associação Genômica Ampla , Humanos , Peixe-Zebra
8.
Transl Psychiatry ; 8(1): 284, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30563984

RESUMO

It is well-established that there is a strong genetic contribution to the aetiology of attention deficit hyperactivity disorder (ADHD). Here, we employed a hypothesis-free genome-wide association study (GWAS) design in a sample of 480 clinical childhood ADHD cases and 1208 controls to search for novel genetic risk loci for ADHD. DNA was genotyped using Illumina's Human Infinium PsychArray-24v1.2., and the data were subsequently imputed to the 1000 Genomes reference panel. Rigorous quality control and pruning of genotypes at both individual subject and single nucleotide polymorphism (SNP) levels was performed. Polygenic risk score (PGRS) analysis revealed that ADHD case-control status was explained by genetic risk for ADHD, but no other major psychiatric disorders. Logistic regression analysis was performed genome-wide to test the association between SNPs and ADHD case-control status. We observed a genome-wide significant association (p = 3.15E-08) between ADHD and rs6686722, mapped to the Tenascin R (TNR) gene. Members of this gene family are extracellular matrix glycoproteins that play a role in neural cell adhesion and neurite outgrowth. Suggestive evidence of associations with ADHD was observed for an additional 111 SNPs (⩽9.91E-05). Although intriguing, the association between DNA variation in the TNR gene and ADHD should be viewed as preliminary given the small sample size of this discovery dataset.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Tenascina
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