RESUMEN
Aberrant protein aggregation jeopardizes cellular functionality and underlies the development of a myriad of late-onset maladies including Alzheimer's disease (AD) and Huntington's disease (HD). Accordingly, molecules that mitigate the toxicity of hazardous protein aggregates are of great interest as potential future therapeutics. Here we asked whether a small peptide, composed of five amino acids (5MER peptide) that was derived from the human pro-inflammatory CD44 protein, could protect model nematodes from the toxicity of aggregative proteins that underlie the development of neurodegenerative disorders in humans. We found that the 5MER peptide mitigates the toxicity that stems from both; the AD-causing Aß peptide and a stretch of poly-glutamine that is accountable for the development of several disorders including HD, while minimally affecting lifespan. This protection was dependent on the activity of aging-regulating transcription factors and associated with enhanced Aß and polyQ35-YFP aggregation. A transcriptomic analysis unveiled that the peptide modifies signaling pathways, thereby modulating the expression of various genes, including these, which are known as protein homeostasis (proteostasis) regulators such as txt-13 and modifiers of proteasome activity. The knockdown of txt-13 protects worms from proteotoxicity to the same extent as the 5MER peptide, suggesting that the peptide activates the transcellular chaperone signaling to promote proteostasis. Together, our results propose that the 5MER peptide should be considered as a component of future therapeutic cocktails for the treatment of neurodegenerative maladies.
Asunto(s)
Enfermedad de Alzheimer , Caenorhabditis elegans , Animales , Humanos , Caenorhabditis elegans/genética , Péptidos beta-Amiloides/toxicidad , Péptidos beta-Amiloides/metabolismo , Factores de Transcripción/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , EnvejecimientoRESUMEN
Neurodegenerative disease (ND) research is producing new pharmaceutical compounds for chronic diseases utilizing bioinformatics. Algorithmic data mining of high-throughput omics systems is conjoined with the study of the in vitro dynamics of protein folding through visualization techniques, i.e., Bio-AFM. Novel models of disease pathway diagrams are being produced and the processes are in place to enhance the validation of these models. From bench work to BLAST to bedside, globally standardized research is led by collaborative clusters, working on cloud-based platforms, with crowd sourced human cohort collections, pairing pure, curiosity-based neurological research with deep learning data analysis techniques. ND research is leading the way towards clinical applications for preventing, curing, or ameliorating major diseases of neurological dysfunction, such as Alzheimer's disease (AD) and Parkinson's disease (PD).Most of this is too complex for the average citizen to comprehend. Can bioart and data-art contribute to the public understanding of genome sequencing and bioinformatics databases in the context of ND research? Informal studies towards demystifying bioinformatics through creative practices have been tested, revealing significant qualitative benefits for public well-being while introducing bioinformatics databases, for instance, previous projects: the VASTAL Bioinformatics and Literary Studies: (De)Mystified Genetic Code Lab, held at the Waag in Amsterdam, NL, 2009 and more recently the Creative Germline Constructs Bank (CGCB) of the transgenic human Genome Alternatives Project (thGAP), held at Hackteria ZET, Zurich, Switzerland, 2021.For the Hub of Art Laboratories (HAL), of the Department of Audio & Visual Arts (AVArts), Ionian University in Corfu, Greece, the animation node is challenged to create audiovisual, immersive, and interactive environments that highlight natural processes and phenomena of the microcosm and macrocosm through nature/data interface experimentation. It is the intention of the node's researchers to expand these notions to be inclusive of the processes of the biotechnological and bioinformatics interrogation of human disease as a part of local clades and global nature. In our productions, we would like to emphasize: cryogenic storage, genome analysis, bioinformatic database management, biomarkers for polygenic abnormalities, genotyping/phenotyping, gene expression patterns over time, AI reading of cloud-based research, experiencial DNA/RNA synthesis, the development of novel DNA, RNA and protein-based therapeutic agents for biomedical applications and CRISPR construct design for model organisms. It is the HAL animation node's goal to design and explore bioart-based, hands-on public workshops that mix bioinformatics and data-art with in-depth knowledge of the scientific community around ND research bodies.To develop these labs, dedicated artistic research is required to be undertaken through laboratory immersion, interactions with scientists, and hands-on experience in the lab. Artists must experience scientific processes through residencies in labs to learn both how to convey the techniques and the social implications of novel methodologies. Artists developing bioart workshops that can introduce non-specialists to a dizzying array of research methodologies need to know what they are talking about. It takes experience and dedication to convey simplified versions of real-time biosensor data, automated histology, clinical databases of medical case studies (anonymized clients), real-time PCR, novel diagnostic biomarker development, etc. As qualitative researchers, artists in labs ensure creative yet informed art and science (SciArt) outcomes able to stimulate public debate through unorthodox education and accurate playfulness. Obviously, the immersive experience of lab research provides an artist's projects with both nuance and knowledge. How can artists in labs also add to the scientific potentials of a laboratory's research goals?
Asunto(s)
Arte , Enfermedades Neurodegenerativas , Animales , Humanos , Enfermedades Neurodegenerativas/genética , Biología Computacional , Animales Modificados Genéticamente , BiotecnologíaRESUMEN
Several neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau post-translational modifications such as phosphorylation and acetylation are increased in neurodegeneration. Here, we show that Tau hyper-acetylation at residue 174 increases its own nuclear presence and is the result of DNA damage signaling or the lack of SIRT6, both causative of neurodegeneration. Tau-K174ac is deacetylated in the nucleus by SIRT6. However, lack of SIRT6 or chronic DNA damage results in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression, affecting protein translation, synthesis, and energy production. Concomitantly, Alzheimer's disease (AD) case subjects show increased nucleolin and a decrease in SIRT6 levels. AD case subjects present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD case subjects is the result of DNA damage signaling and SIRT6 depletion. We propose that Tau-K174ac toxicity is due to its increased stability, nuclear accumulation, and nucleolar dysfunction.
Asunto(s)
Enfermedad de Alzheimer/genética , Biosíntesis de Proteínas/genética , Sirtuinas/metabolismo , Proteínas tau/metabolismo , Humanos , Sirtuinas/genéticaRESUMEN
Public experimental embryology opens a relationship between an embryo and an amateur transgenic designer. Artists produce real-world effects by forcing hereditary aesthetics on developing bodies. This lab was meant to aid in public understanding of the relationship between transgenics and aesthetics. How do we to take an active and hands-on tactical stance on the role of hereditary designer and how does this help in public analysis of the bioethics of genetic engineering. Through naming and funeral rites, we assign the embryos an uncertain amount of clout or cultural worth. This lab is an example of how to understand the relationship between institutional oversight in pre-animal experimentation, embryonic dignity, and the problem of humane sacrifice. The intention is to make a hands-on wet bioart lab meant to aid in public comprehension of the range of politics and responsibilities involved in play at the level of heredity. The Developmental Biology and Transgenic Avian Embryology Bioart Wet Lab was held in Gorlaeus Laboratories, LIC, University of Leiden, Leiden, Netherlands, 2007.