RESUMO
Amyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with currently no cure. These two diseases share a clinical continuum with overlapping genetic causes. Mutations in the CHMP2B gene are found in patients with ALS, FTD and ALS-FTD. To highlight deregulated mechanisms occurring in ALS-FTD linked to the CHMP2B gene, we performed a whole transcriptomic study on lumbar spinal cord from CHMP2Bintron5 mice, a model that develops progressive motor alterations associated with dementia symptoms reminiscent of both ALS and FTD. To gain insight into the transcriptomic changes taking place during disease progression this study was performed at three stages: asymptomatic, symptomatic and end stage. We showed that before appearance of motor symptoms, the major disrupted mechanisms were linked with the immune system/inflammatory response and lipid metabolism. These processes were progressively replaced by alterations of neuronal electric activity as motor symptoms appeared, alterations that could lead to motor neuron dysfunction. To investigate overlapping alterations in gene expression between two ALS-causing genes, we then compared the transcriptome of symptomatic CHMP2Bintron5 mice with the one of symptomatic SOD1G86R mice and found the same families deregulated providing further insights into common underlying dysfunction of biological pathways, disrupted or disturbed in ALS. Altogether, this study provides a database to explore potential new candidate genes involved in the CHMP2Bintron5-based pathogenesis of ALS, and provides molecular clues to further understand the functional consequences that diseased neurons expressing CHMP2B mutant may have on their neighbor cells.
Assuntos
Esclerose Lateral Amiotrófica/genética , Modelos Animais de Doenças , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Demência Frontotemporal/genética , Proteínas do Tecido Nervoso/genética , Superóxido Dismutase-1/genética , Transcriptoma/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Complexos Endossomais de Distribuição Requeridos para Transporte/biossíntese , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/biossíntese , Medula Espinal/metabolismo , Medula Espinal/patologiaRESUMO
The assessment of toxic effects at biologically and ecologically relevant scales is an important challenge in ecosystem protection. Indeed, stressors may impact populations at much longer term than the usual timescale of toxicity tests. It is therefore important to study the evolutionary response of a population under chronic stress. We performed a 16-generation study to assess the evolution of two populations of the ubiquitous nematode Caenorhabditis elegans in control conditions or exposed to 1.1 mM of uranium. Several generations were selected to assess growth, reproduction, survival, and dose-responses relationships, through exposure to a range of concentrations (from 0 to 1.2 mM U) with all endpoints measured daily. Our experiment showed an adaptation of individuals to experimental conditions (increase of maximal length and decrease of fecundity) for both populations. We also observed an increase of adverse effects (reduction of growth and fertility) as a function of uranium concentration. We pointed out the emergence of population differentiation for reproduction traits. In contrast, no differentiation was observed on growth traits. Our results confirm the importance of assessing environmental risk related to pollutant through multi-generational studies.
Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Estágios do Ciclo de Vida/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Compostos de Urânio/toxicidade , Adaptação Fisiológica/genética , Animais , Tamanho Corporal/efeitos dos fármacos , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/genética , Relação Dose-Resposta a Droga , Fertilidade/efeitos dos fármacos , Interação Gene-Ambiente , Longevidade/efeitos dos fármacos , Reprodução/genética , Medição de RiscoRESUMO
This study examined chronic effects of external Cs-137 gamma radiation on Daphnia magna exposed over three successive generations (F0, F1 and F2) to environmentally relevant dose rates (ranging from 0.007 to 35.4 mGy h(-1)). Investigated endpoints included survival, growth, reproduction and DNA alterations quantified using random-amplified polymorphic DNA polymerase chain reaction (RAPD-PCR). Results demonstrated that radiation effects on survival, growth and reproduction increased in severity from generation F0 to generation F2. Mortality after 21 days at 35.4 mGy h(-1) increased from 20% in F0 to 30% in F2. Growth was affected by a slight reduction in maximum length at 35.4 mGy h(-1) in F0 and by reductions of 5 and 13% in growth rate, respectively, at 4.70 and 35.4 mGy h(-1) in F2. Reproduction was affected by a reduction of 19% in 21 day-fecundity at 35.4 mGy h(-1) in F0 and by a delay of 1.9 days in brood release as low as 0.070 mGy h(-1) in F2. In parallel, DNA alterations became significant at decreasing dose rates over the course of F0 (from 4.70 mGy h(-1) at hatching to 0.007 mGy h(-1) after â¼21 days) and from F0 to F2 (0.070 mGy h(-1) at hatching to 0.007 mGy h(-1) after â¼21 days), demonstrating their rapid accumulation in F0 daphnids and their transmission to offspring generations. Transiently more efficient DNA repair leading to some recovery at the organism level was suggested in F1, with no effect on survival, a slight reduction of 12% in 21 day-fecundity at 35.4 mGy h(-1) and DNA alterations significant at highest dose rates only. The study improved our understanding of long term responses to low doses of radiation at the molecular and organismic levels in a non-human species for a better radioprotection of aquatic ecosystems.