RESUMEN
Over the past decade, the baker's yeast Saccharomyces cerevisiae has proven to be a useful model system to investigate fundamental questions concerning the pathogenic role of human proteins in neurodegenerative diseases such as Parkinson's disease (PD). These so-called humanized yeast models for PD initially focused on α -synuclein, which plays a key role in the etiology of PD. Upon expression of this human protein in the baker's yeast Saccharomyces cerevisiae, the events leading to aggregation and the molecular mechanisms that result in cellular toxicity are faithfully reproduced. More recently, a similar model to study the presumed pathobiology of the α -synuclein interaction partner synphilin-1 has been established. In this review we will discuss recent advances using these humanized yeast models, pointing to new roles for cell wall integrity signaling, Ca(2+) homeostasis, mitophagy, and the cytoskeleton.
Asunto(s)
Enfermedad de Parkinson/metabolismo , Saccharomyces cerevisiae/metabolismo , Humanos , Saccharomyces cerevisiae/genética , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, which arises from a yet elusive concurrence between genetic and environmental factors. The protein α-synuclein (αSyn), the principle toxic effector in PD, has been shown to interfere with neuronal Ca(2+) fluxes, arguing for an involvement of deregulated Ca(2+) homeostasis in this neuronal demise. Here, we identify the Golgi-resident Ca(2+)/Mn(2+) ATPase PMR1 (plasma membrane-related Ca(2+)-ATPase 1) as a phylogenetically conserved mediator of αSyn-driven changes in Ca(2+) homeostasis and cytotoxicity. Expression of αSyn in yeast resulted in elevated cytosolic Ca(2+) levels and increased cell death, both of which could be inhibited by deletion of PMR1. Accordingly, absence of PMR1 prevented αSyn-induced loss of dopaminergic neurons in nematodes and flies. In addition, αSyn failed to compromise locomotion and survival of flies when PMR1 was absent. In conclusion, the αSyn-driven rise of cytosolic Ca(2+) levels is pivotal for its cytotoxicity and requires PMR1.
Asunto(s)
ATPasas Transportadoras de Calcio/metabolismo , Calcio/metabolismo , Modelos Biológicos , Proteínas de Saccharomyces cerevisiae/metabolismo , alfa-Sinucleína/metabolismo , Acetilcisteína/farmacología , Animales , Apoptosis , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , ATPasas Transportadoras de Calcio/deficiencia , ATPasas Transportadoras de Calcio/genética , Humanos , Manganeso/metabolismo , Chaperonas Moleculares , Estrés Oxidativo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Fosforilación , Regiones Promotoras Genéticas , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , alfa-Sinucleína/genética , alfa-Sinucleína/toxicidadRESUMEN
The budding yeast Saccharomyces cerevisiae has contributed significantly to our current understanding of eukaryotic cell biology. It served as a tool and model for unraveling the molecular basis of a wide variety of cellular phenomena, which seem to be conserved in other organisms. During the last decade, yeast has also extensively been used to study the mechanisms underlying several human diseases, including age-associated neurodegenerative disorders, such as Parkinson's, Huntington's and Alzheimer's disease. In this review, we focus on a yeast model for synucleinopathies and summarize recent studies that not only provided new clues on how the misfolding of alpha-synuclein (alpha-syn) triggers toxicity and eventually cell death, but that also led to the identification of conserved suppressor proteins, which are effective in protecting cells, including neurons, from the alpha-syn-induced cytotoxicity.
Asunto(s)
Apoptosis/fisiología , Levaduras/citología , Levaduras/metabolismo , alfa-Sinucleína/metabolismo , Animales , Humanos , Modelos Biológicos , Estrés Oxidativo/fisiología , Enfermedad de Parkinson/metabolismoRESUMEN
In different parts of the world, locust swarms cause severe ecological and economic damage. However, the physiological mechanisms underlying this gregarization process remain elusive. In this study, we present a detailed quantitative analysis of two neuroparsin precursor (Scg-NPP1 and Scg-NPP2) transcripts in the brain, fat body, gut, gonads and accessory glands of male and female, gregarious and solitarious desert locusts (Schistocerca gregaria). These transcripts are generally more abundant in solitarious than in gregarious animals. In contrast to their gregarious congeners, solitarious locusts contain detectable Scg-NPP1 and Scg-NPP2 transcript levels in the fat body. Moreover, our data reveal temporal changes of neuroparsin mRNA levels in the brains and fat bodies of adult isolated-reared locusts. This paper provides the first scientific evidence for phase-dependent transcriptional regulation of neuropeptide hormone encoding genes.
Asunto(s)
Saltamontes/metabolismo , Hormonas de Insectos/biosíntesis , Animales , Encéfalo/metabolismo , Cuerpo Adiposo/fisiología , Femenino , Saltamontes/genética , Hormonas de Insectos/genética , Masculino , ARN/química , ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcripción Genética/fisiologíaRESUMEN
This review summarizes recent advances and novel concepts in the area of insect reproductive neuroendocrinology. The role of 'classic' hormones, such as ecdysteroids and juvenoids, to control reproduction is well documented in a large variety of insect species. In adult gonads, ecdysteroids appear to induce a cascade of transcription factors, many of which also occur during the larval molting response. Recent molecular and functional data have created opportunities to study an additional level of regulation, that of neuropeptides, growth factors and their respective receptors. As a result, many homologs of factors playing a role in vertebrate reproductive physiology have been discovered in insects. This review highlights several neuropeptides controlling the biosynthesis and release of the 'classic' insect hormones, as well as various peptides and biogenic amines that regulate behavioural aspects of the reproduction process. In addition, hormone metabolizing enzymes and second messenger pathways are discussed with respect to their role in reproductive tissues. Finally, we speculate on future prospects for insect neuroendocrinological research as a consequence of the recent 'Genomics Revolution'.