Telethon Institute of Genetics and Medicine

Napoli, Italy

Telethon Institute of Genetics and Medicine

Napoli, Italy
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Martini-Stoica H.,Baylor College of Medicine | Xu Y.,Baylor College of Medicine | Ballabio A.,Baylor College of Medicine | Ballabio A.,The Texas Institute | And 2 more authors.
Trends in Neurosciences | Year: 2016

The autophagy-lysosomal pathway (ALP) is involved in the degradation of long-lived proteins. Deficits in the ALP result in protein aggregation, the generation of toxic protein species, and accumulation of dysfunctional organelles, which are hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and prion disease. Decades of research have therefore focused on enhancing the ALP in neurodegenerative diseases. More recently, transcription factor EB (TFEB), a major regulator of autophagy and lysosomal biogenesis, has emerged as a leading factor in addressing disease pathology. We review the regulation of the ALP and TFEB and their impact on neurodegenerative diseases. We also offer our perspective on the complex role of autophagy and TFEB in disease pathogenesis and its therapeutic implications through the examination of prion disease. © 2016.

Napolitano F.,Telethon Institute of Genetics and Medicine
BMC Bioinformatics | Year: 2017

Background: Reproducibility in Data Analysis research has long been a significant concern, particularly in the areas of Bioinformatics and Computational Biology. Towards the aim of developing reproducible and reusable processes, Data Analysis management tools can help giving structure and coherence to complex data flows. Nonetheless, improved software quality comes at the cost of additional design and planning effort, which may become impractical in rapidly changing development environments. I propose that an adjustment of focus from processes to data in the management of Bioinformatic pipelines may help improving reproducibility with minimal impact on preexisting development practices. Results: In this paper I introduce the repo R package for bioinformatic analysis management. The tool supports a data-centered philosophy that aims at improving analysis reproducibility and reusability with minimal design overhead. The core of repo lies in its support for easy data storage, retrieval, distribution and annotation. In repo the data analysis flow is derived a posteriori from dependency annotations. Conclusions: The repo package constitutes an unobtrusive data and flow management extension of the R statistical language. Its adoption, together with good development practices, can help improving data analysis management, sharing and reproducibility, especially in the fields of Bioinformatics and Computational Biology. © 2017 The Author(s).

Fraldi A.,Telethon Institute of Genetics and Medicine | Klein A.D.,Telethon Institute of Genetics and Medicine | Medina D.L.,Telethon Institute of Genetics and Medicine | Settembre C.,Telethon Institute of Genetics and Medicine | And 2 more authors.
Annual Review of Neuroscience | Year: 2016

Recent studies of autophagic and lysosomal pathways have significantly changed our understanding of lysosomes; once thought to be simple degradative and recycling centers, lysosomes are now known to be organelles capable of influencing signal transduction, via the mammalian target of rapamycin complex 1 (mTORC1), and regulating gene expression, via transcription factor EB (TFEB) and other transcription factors. These pathways are particularly relevant to maintaining brain homeostasis, as dysfunction of the endolysosomal and autophagic pathways has been associated with common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's, and lysosomal storage disorders, a group of inherited disorders characterized by the intralysosomal buildup of partially degraded metabolites. This review focuses on the cellular biology of lysosomes and discusses the possible mechanisms by which disruption of their function contributes to neurodegeneration. We also review and discuss how targeting TFEB and lysosomes may offer innovative therapeutic approaches for treating a wide range of neurological conditions. Copyright ©2016 by Annual Reviews.

Nakano A.,University of Tokyo | Nakano A.,RIKEN | Luini A.,Telethon Institute of Genetics and Medicine
Current Opinion in Cell Biology | Year: 2010

There are, in theory, several ways in which proteins may pass through the Golgi apparatus. Among these, the cisternal progression-maturation mode has gained broad consensus. However, there remain questions regarding the molecular mechanisms by which resident proteins are sorted from cargo and move backward to the proximal cisterna in synchrony with cisternal progression. In this short review, we discuss current questions about the organisation of trafficking to, through, and out of the Golgi apparatus, as well as the main approaches being developed to address such questions in model organisms including yeast, mammals and plants. © 2010 Elsevier Ltd.

De Matteis M.A.,Telethon Institute of Genetics and Medicine | Luini A.,Telethon Institute of Genetics and Medicine | Luini A.,National Research Council Italy
New England Journal of Medicine | Year: 2011

It is reasonable to hope that our basic knowledge of membrane trafficking will continue to provide insights into the pathogenesis of mendelian diseases and that studies of these diseases will continue to enhance our understanding of the membrane- trafficking system. In particular, it will be of great interest in this context to learn how to place the genes that are involved in trafficking-related diseases into coherent pathogenetic pathways. Regrettably, the wealth of new insights into the molecular defects in membrane-trafficking disorders has not yet led to a proportionate availability availability of effective therapies. However, in the past few years, the potential of mendelian diseases to drive the process of drug development has been recognized. 52,53 An example in the field of membrane transport is cystic fibrosis. Effective modulators of the folding, trafficking, and activity of CFTR (the chloride channel that is mutated in cystic fibrosis35) have been found through high-throughput screening that was aimed at identifying pharmacologic treatments for this disease. Some of these modulators (e.g., VX-809) are now being tested in clinical trials.54 In addition, interest in the pathways affected in mendelian disorders is being raised further by the recognition that efforts to develop drugs for their treatment might also prove useful in common diseases in which the same pathways might have a pathogenetic role, such as type 2 diabetes and Alzheimer's disease. 52,53 Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Venditti R.,Telethon Institute of Genetics and Medicine | Wilson C.,Telethon Institute of Genetics and Medicine | De Matteis M.A.,Telethon Institute of Genetics and Medicine
Trends in Cell Biology | Year: 2014

The vast majority of proteins that are transported to different cellular compartments and secreted from the cell require coat protein complex II (COPII) for export from the endoplasmic reticulum (ER). Many of the molecular mechanisms underlying COPII assembly are understood in great detail, but it is becoming increasingly evident that this basic machinery is insufficient to account for diverse aspects of protein export from the ER that are observed in vivo. Here we review recent data that have furthered our mechanistic understanding of COPII assembly and, in particular, how genetic diseases associated with the early secretory pathway have added fundamental insights into the regulation of ER-derived carrier formation. We also highlight some unresolved issues that future work should address to better understand the physiology of COPII-mediated transport. © 2013 Elsevier Ltd.

de Leo M.G.,Telethon Institute of Genetics and Medicine
Nature Cell Biology | Year: 2016

Phosphoinositides (PtdIns) control fundamental cell processes, and inherited defects of PtdIns kinases or phosphatases cause severe human diseases, including Lowe syndrome due to mutations in OCRL, which encodes a PtdIns(4,5)P2 5-phosphatase. Here we unveil a lysosomal response to the arrival of autophagosomal cargo in which OCRL plays a key part. We identify mitochondrial DNA and TLR9 as the cargo and the receptor that triggers and mediates, respectively, this response. This lysosome-cargo response is required to sustain the autophagic flux and involves a local increase in PtdIns(4,5)P2 that is confined in space and time by OCRL. Depleting or inhibiting OCRL leads to an accumulation of lysosomal PtdIns(4,5)P2, an inhibitor of the calcium channel mucolipin-1 that controls autophagosome–lysosome fusion. Hence, autophagosomes accumulate in OCRL-depleted cells and in the kidneys of Lowe syndrome patients. Importantly, boosting the activity of mucolipin-1 with selective agonists restores the autophagic flux in cells from Lowe syndrome patients. © 2016 Nature Publishing Group

Nigro V.,Telethon Institute of Genetics and Medicine | Savarese M.,Telethon Institute of Genetics and Medicine
Acta Myologica | Year: 2014

Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of muscle disorders, which first affect the voluntary muscles of the hip and shoulder areas. The definition is highly descriptive and less ambiguous by exclusion: non-Xlinked, non-FSH, non-myotonic, non-distal, nonsyndromic, and non-congenital. At present, the genetic classification is becoming too complex, since the acronym LGMD has also been used for a number of other myopathic disorders with overlapping phenotypes. Today, the list of genes to be screened is too large for the gene-by-gene approach and it is well suited for targeted next generation sequencing (NGS) panels that should include any gene that has been so far associated with a clinical picture of LGMD. The present review has the aim of recapitulating the genetic basis of LGMD ordering and of proposing a nomenclature for the orphan forms. This is useful given the pace of new discoveries. Thity-one loci have been identified so far, eight autosomal dominant and 23 autosomal recessive. The dominant forms (LGMD1) are: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin 3), LGMD1D (DNAJB6), LGMD1E (desmin), LGMD1F (transportin 3), LGMD1G (HNRPDL), LGMD1H (chr. 3). The autosomal recessive forms (LGMD2) are: LGMD2A (calpain 3), LGMD2B (dysferlin), LGMD2C (? sarcoglycan), LGMD2D (a sarcoglycan), LGMD2E (β sarcoglycan), LGMD2F (d sarcoglycan), LGMD2G (telethonin), LGMD2H (TRIM32), LGMD2I (FKRP), LGMD2J (titin), LGMD2K (POMT1), LGMD2L (anoctamin 5), LGMD2M (fukutin), LGMD2N (POMT2), LGMD2O (POMTnG1), LGMD2P (dystroglycan), LGMD2Q (plectin), LGMD2R (desmin), LGMD2S (TRAPPC11), LGMD2T (GMPPB), LGMD2U (ISPD), LGMD2V (Glucosidase, alpha ), LGMD2W (PINCH2).

De Matteis M.A.,Telethon Institute of Genetics and Medicine | Rega L.R.,Bambino Gesu Childrens Hospital Scientific Institute
Current Opinion in Cell Biology | Year: 2015

Although they were identified as long ago as the 1960s, there are still many unknowns regarding the functions and composition of membrane contact sites between the endoplasmic reticulum (ER) and the trans-Golgi (TG). While it seems to be fairly well established that they facilitate lipid exchange between the two organelles, much less is known about how they are regulated. A bottleneck in the study of the ER-TG contact sites has been the absence of methods for their biochemical isolation and visualization by light microscopy. Herein we provide an overview of current knowledge about ER-TG contact sites with a particular emphasis on the questions that remain to be explored. © 2015.

Glick B.S.,University of Chicago | Luini A.,Telethon Institute of Genetics and Medicine
Cold Spring Harbor Perspectives in Biology | Year: 2011

Avariety of secretory cargoes move through the Golgi, but the pathways and mechanisms of this traffic are still being debated. Here, we evaluate the strengths and weaknesses of five current models for Golgi traffic: (1) anterograde vesicular transport between stable compartments, (2) cisternal progression/maturation, (3) cisternal progression/maturation with heterotypic tubular transport, (4) rapid partitioning in a mixed Golgi, and (5) stable compartments as cisternal progenitors. Each model is assessed for its ability to explain a set of key observations encompassing multiple cell types. No single model can easily explain all of the observations from diverse organisms. However, we propose that cisternal progression/ maturation is the best candidate for a conserved core mechanism of Golgi traffic, and that some cells elaborate this core mechanism by means of heterotypic tubular transport between cisternae. © 2011 Cold Spring Harbor Laboratory Press.

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