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Andrea Ballabio

Scientific Director, TIGEM
Principal Investigator, TIGEM

Professor of Medical Genetics, Department of Translational Medicine, University of Naples "Federico II", Italy.
Professor, Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Houston, TX, USA.

Modulating Cellular Clearance to treat human disease

Cellular clearance is a fundamental process required by the cells of every species. In eukaryotes, most of the cellular clearing processes occur in a specialized organelle, the lysosome. Given that the requirements of the degradative machinery in a cell may vary depending on tissue type, age and environmental conditions, we postulated that a system coordinates lysosomal activity and that lysosomal function is subject to transcriptional regulation. Using a systems biology-based approach, we discovered a gene regulatory network (CLEAR: Coordinated Lysosomal Enhancement And Regulation) that controls lysosomal biogenesis and function (Sardiello et al, Science 2009) and a master gene, the bHLH-leucine zipper transcription factor TFEB, which binds to CLEAR target sites in the promoter of lysosomal genes and positively regulates their expression (Sardiello et al, Science 2009). TFEB overexpression induces lysosomal biogenesis and increases the cell’s ability to degrade complex molecules such as mutated huntingtin in a cellular model of Huntington’s disease. More recent studies performed in our laboratory have shown that TFEB directly regulates autophagy, thus indicating that the biogeneses of and autophagosomes, two organelles cooperating in cellular clearance, are linked (Settembre et al., Science, 2011).  We also demonstrated that TFEB is able to promote cellular clearance in several murine models of LSDs, both in cell culture and in vivo (Medina et al, Dev Cell, 2011). The same approach was subsequently used by several investigators to promote clearance of accumulating toxic substrates in a broad variety of diseases, such as Parkinson’s, Alzheimer’s, Huntington’s disease, α 1-anti-trypsin deficiency, and Spinal Bulbar Muscular Atrophy. Finally, we have made significant progress in understanding the way in which TFEB is regulated. We demonstrated that TFEB colocalizes with the master growth regulator kinase mTOR on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTOR inhibits TFEB activity (Settembre et al., EMBOJ., 2012). Conversely, pharmacological inhibition of mTOR, as well as starvation and lysosomal disruption, may activate TFEB by promoting its nuclear translocation (Settembre et al., EMBOJ., 2012).  We have also demonstrated that TFEB is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism (Settembre et al., Nature Cell Biology, 2013).

These findings provide us with the understanding to use novel and innovative tools and strategies to promote cellular clearance. The regulation of lysosome-mediated cellular clearance is a new concept in cell biology. Our laboratory is now focused on the study of the regulation and activation of TFEB and on determining mechanisms to activate TFEB function utilizing cell culture systems and in vivo animal models. The challenge of our current research project is to develop tools to modulate cellular clearance and to use them to treat human diseases, including Lysosomal Storage Disorders and neurodegenerative diseases such as Huntington’s, Alzheimer’s and Parkinson’s.

Napolitano G*, Di Malta C*, Esposito A, de Araujo M, Pece S, Bertalot G, Matarese M, Benedetti V, Zampelli A, Stasyk T, Siciliano D, Venuta A, Cesana M, Vilardo C, Nusco E, Monfregola J, Calcagnì A, Di Fiore PP, Huber LA & Ballabio A (2020). A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome. Nature. 01 July 2020;

Di Malta C, Siciliano D, Calcagni A, Monfregola J, Punzi S, Pastore N, Eastes AN, Davis O, De Cegli R, Zampelli A, Di Giovannantonio LG, Nusco E, Platt N, Guida A, Ogmundsdottir MH, Lanfrancone L, Perera RM, Zoncu R, Pelicci PG, Settembre C, Ballabio A (2017). Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth Science. 2017 Jun 16;356(6343):1188-1192. doi: 10.1126/science.aag2553.



Full Text

Mansueto G, Armani A, Viscomi C, D'Orsi L, De Cegli R, Polishchuk EV, Lamperti C, Di Meo I, Romanello V, Marchet S, Saha PK, Zong H, Blaauw B, Solagna F, Tezze C, Grumati P, Bonaldo P, Pessin JE, Zeviani M, Sandri M, Ballabio A (2017). Transcription Factor EB Controls Metabolic Flexibility during Exercise. Cell Metab. 25(1):182-196. doi: 10.1016/j.cmet.2016.11.003. Epub 2016 Dec 20.

Medina DL, Di Paola S, Peluso I, Armani A, De Stefani D, Venditti R, Montefusco S, Scotto-Rosato A, Prezioso C, Forrester A, Settembre C, Wang W, Gao Q, Xu H, Sandri M, Rizzuto R, De Matteis MA, Ballabio A (2015). Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat Cell Biol. 17(3):288-99.

Settembre C, De Cegli R, MansuetoG, Saha PK, Vetrini F, Visvikis O., Huynh T, Carissimo A, Palmer D, Klisch TJ., Wollenberg AC, di Bernardo D, Chan L, IrazoquiJ.E, and Ballabio A (2013). TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol.15 (6):647-658. doi: 10.1038/ncb2718. 

Settembre C, Di Malta C, Polito VA, Arencibia MG, Vetrini F, Erdin S, Erdin SU, Huynh T, Medina D, Colella P, Sardiello M, Rubinsztein DC, Ballabio A (2011). TFEB Links Autophagy to Lysosomal BiogenesisScience. 332: 1429-1433. doi: 10.1126/science.1204592.

Andrea Ballabio MD

Cell Biology and Disease Mechanisms

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Fax: +3908119230650