Protective role of chaperone-mediated autophagy against atherosclerosis

Significance Cardiovascular diseases remain the leading cause of death worldwide, with atherosclerosis being the most common source of clinical events. Metabolic changes with aging associate with concurrent increased risk of both type 2 diabetes and cardiovascular disease, with the former further raising the risk of the latter. The activity of a selective type of autophagy, chaperone-mediated autophagy (CMA), decreases with age or upon dietary excesses. Here we study whether reduced CMA activity increases risk of atherosclerosis in mouse models. We have identified that CMA is up-regulated early in response to proatherogenic challenges and demonstrate that reduced systemic CMA aggravates vascular pathology in these conditions. We also provide proof-of-concept support that CMA up-regulation is an effective intervention to reduce atherosclerosis severity and progression

Protective role of chaperone-mediated autophagy against atherosclerosis

Chaperone-mediated autophagy (CMA) contributes to regulation of energy homeostasis by timely degradation of enzymes involved in glucose and lipid metabolism. Here, we report reduced CMA activity in vascular smooth muscle cells and macrophages in murine and human arteries in response to atherosclerotic challenges. We show that in vivo genetic blockage of CMA worsens atherosclerotic pathology through both systemic and cell-autonomous changes in vascular smooth muscle cells and macrophages, the two main cell types involved in atherogenesis. CMA deficiency promotes dedifferentiation of vascular smooth muscle cells and a proinflammatory state in macrophages. Conversely, a genetic mouse model with up-regulated CMA shows lower vulnerability to proatherosclerotic challenges. We propose that CMA could be an attractive therapeutic target against cardiovascular diseases

II Congrés Internacional sobre Traducció : abril 1994 : actes

Machine learning-based approach unravels distinct pathological signatures induced by patient-derived α-synuclein seeds in monkeys. Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)-rich protein aggregates [termed "Lewy bodies" (LBs)], is a well-established characteristic of Parkinson's disease (PD). Much evidence, accumulated from multiple experimental models, has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here, we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from patients with PD. Unexpectedly, our results show that, in nonhuman primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD, as multiple causes can induce a similar outcome regarding dopaminergic neurodegeneratio

Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms

Uncovering tomato quantitative trait loci and candidate genes for fruit cuticular lipid composition using the Solanum pennellii introgression line population

[EN] The cuticle is a specialized cell wall layer that covers the outermost surface of the epidermal cells and has important implications for fruit permeability and pathogen susceptibility. In order to decipher the genetic control of tomato fruit cuticle composition, an introgression line (IL) population derived from a biparental cross between Solanum pennellii (LA0716) and the Solanum lycopersicum cultivar M82 was used to build a first map of associated quantitative trait loci (QTLs). A total of 24 cuticular waxes and 26 cutin monomers were determined. They showed changes associated with 18 genomic regions distributed in nine chromosomes affecting 19 ILs. Out of the five main fruit cuticular components described for the wild species S. pennellii, three of them were associated with IL3.4, IL12.1, and IL7.4.1, causing an increase in n-alkanes (>= C-30), a decrease in amyrin content, and a decrease in cuticle thickness of similar to 50%, respectively. Moreover, we also found a QTL associated with increased levels of amyrins in IL3.4. In addition, we propose some candidate genes on the basis of their differential gene expression and single nucleotide polymorphism variability between the introgressed and the recurrent alleles, which will be the subjects of further investigation.Research at the IBMCP was supported by the Spanish Ministry of Education and Culture (BIO2013-42193-R) and H2020 TRADITOM (634561). AA, AG, and J-PF-M thank COST FA1106 Quality Fruit for STSM and networking activities. This work was supported by the Israel Science Foundation (ISF) personal grant to AA (grant no. 646/11). We would like to thank the Adelis Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, the Jeanne and Joseph Nissim Foundation for Life Sciences, Tom and Sondra Rykoff Family Foundation Research, and the Raymond Burton Plant Genome Research Fund for supporting AA's laboratory activity. AA is the incumbent of the Peter J. Cohn Professorial Chair. We are very grateful to Prof. Dani Zamir for providing us the S. pennellii IL collection and to Prof. Antonio Heredia for his valuable advice in preparing the manuscript for publication. We would like to acknowledge the help offered by the Electron Microscopy Unit at the WIS (Israel) for the TEM sample preparation and imaging, especially Elena Kartvelishvily, Eugenia Klein, and Eyal Shimoni. Finally, we would also like to thank Calanit Raanan and Tamara Berkutzki (Department of Veterinary Resources, WIS) for their help in tissue fixation and embedding, as well as Hanna Levanony (Department of Plant Sciences, WIS) for her help in tissue staining for the light microscopy studies.Fernández Moreno, JP.; Levy-Samoha, D.; Malitsky, S.; Monforte Gilabert, AJ.; Orzáez Calatayud, DV.; Aharoni, A.; Granell Richart, A. (2017). Uncovering tomato quantitative trait loci and candidate genes for fruit cuticular lipid composition using the Solanum pennellii introgression line population. Journal of Experimental Botany. 68(11):2703-2716. https://doi.org/10.1093/jxb/erx134S27032716681

Mitochondrial division inhibitor-1 is neuroprotective in the A53T-α-synuclein rat model of Parkinson’s disease

Alpha-synuclein (α-syn) is involved in both familial and sporadic Parkinson’s disease (PD). One of the proposed pathogenic mechanisms of α-syn mutations is mitochondrial dysfunction. However, it is not entirely clear the impact of impaired mitochondrial dynamics induced by α-syn on neurodegeneration and whether targeting this pathway has therapeutic potential. In this study we evaluated whether inhibition of mitochondrial fission is neuroprotective against α-syn overexpression in vivo. To accomplish this goal, we overexpressed human A53T-α- synuclein (hA53T-α-syn) in the rat nigrostriatal pathway, with or without treatment using the small molecule Mitochondrial Division Inhibitor-1 (mdivi-1), a putative inhibitor of the mitochondrial fission Dynamin-Related Protein-1 (Drp1). We show here that mdivi-1 reduced neurodegeneration, α-syn aggregates and normalized motor function. Mechanistically, mdivi-1 reduced mitochondrial fragmentation, mitochondrial dysfunction and oxidative stress. These in vivo results support the negative role of mutant α-syn in mitochondrial function and indicate that mdivi-1 has a high therapeutic potential for PD

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches-hypothesis-based candidate molecule testing and hypothesis-free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.Project ON.2 SR&TD Integrated Program (NORTE-07-0124-FEDER-000021), co-funded by North Portugal Regional Operational Program (ON.2-O Novo Norte), under the National Strategic Reference Framework, through the European Regional Development Fund (ERDF) and also supported by Fundação para a Ciência e Tecnologia through the project POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014)info:eu-repo/semantics/publishedVersio

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field