Article
Biochemistry & Molecular Biology
Kailash Ramlaul, Wencheng Fu, Hua Li, Natalia de Martin Garrido, Lin He, Manjari Trivedi, Wei Cui, Christopher H. S. Aylett, Geng Wu
Summary: The Tuberous Sclerosis Complex (TSC) protein complex (TSCC) is crucial for cell growth and stress signal integration upstream of mTORC1, by acting as a GAP towards Rheb. TSCC has a scorpion-like structure consisting of TSC1 and TSC2, with complex architecture and topology, suggesting a potential role in Rheb-signalling suppression through functional oligomerization.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Adam Pillon, Jessica Dare-Shih, Jackie Fong, Elizabeth Fidalgo da Silva, Lisa A. A. Porter
Summary: Tuberin, a component of the Tuberous Sclerosis Complex, plays a crucial role in cell cycle progression. Mutations in the Tuberin gene can lead to the formation of benign tumors. A study on a truncation of the Tuberin protein shows that it alters the subcellular localization of Cyclin B1 and increases cell proliferation.
Article
Genetics & Heredity
Hirofumi Kashii, Shinya Kasai, Atsushi Sato, Yoko Hagino, Yasumasa Nishito, Toshiyuki Kobayashi, Okio Hino, Masashi Mizuguchi, Kazutaka Ikeda
Summary: The study found that double mutations in the TSC1 and TSC2 genes lead to the occurrence of autism spectrum disorder, similar to TSC2 mutations. The double mutations cause significant changes in gene expression and contribute to the genotype-phenotype correlations in TSC.
Correction
Genetics & Heredity
Krinio Giannikou, Kathryn D. Lasseter, Joannes M. Grevelink, Magdalena E. Tyburczy, Kira A. Dies, Zachary Zhu, Lana Hamieh, Bruce M. Wollison, Aaron R. Thorner, Stephen J. Ruoss, Elizabeth A. Thiele, Mustafa Sahin, David J. Kwiatkowski
Summary: A correction to the paper has been published.
GENETICS IN MEDICINE
(2021)
Review
Cell Biology
E. Fidalgo da Silva, J. Fong, A. Roye-Azar, A. Nadi, C. Drouillard, A. Pillon, L. A. Porter
Summary: The ability of cells to sense environmental signals and integrate them with the cell cycle machinery is critical for cellular function. The Tuberous Sclerosis Complex (TSC) protein complex plays a key role in integrating diverse environmental signals to regulate protein synthesis, cell cycle progression, and other important cell biology events.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Simone Bonazzi, Audrey Gray, Noel M. Thomsen, Jonathan Biag, Nancy Labbe-Giguere, Erin P. Keaney, Hasnain A. Malik, Yingchuan Sun, Jill Nunez, Rajeshri G. Karki, Mark Knapp, Robert Elling, John Fuller, Gwynn Pardee, Lucas Craig, Ketthsy Capre, Sarah Salas, Aakruti Gorde, Guiqing Liang, Danuta Lubicka, Stephanie M. McTighe, Carleton Goold, Shanming Liu, Lin Deng, Jin Hong, Alexander Fekete, Pascal Stadelmann, Wilfried Frieauff, Azeddine Elhajouji, Daniel Bauer, Andreas Lerchner, Branko Radetich, Pascal Furet, Grazia Piizzi, Doug Burdette, Christopher J. Wilson, Stefan Peukert, Lawrence G. Hamann, Leon O. Murphy, Daniel Curtis
Summary: The allosteric inhibitor everolimus reduces seizures in TSC patients by partially inhibiting mTOR functions. However, it has limited brain permeability, so a catalytic mTOR inhibitor optimized for CNS indications was developed. Compound 1 showed genotoxicity risk, but compounds 9 and 11 without genotoxicity risk successfully corrected aberrant mTOR activity and improved the survival rate in the Tsc1 gene knockout model. Unfortunately, compounds 9 and 11 had limited oral exposures and dose-limiting toxicities in cynomolgus macaque, but they remain useful for studying mTOR hyperactivity in CNS disease models.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Medicine, General & Internal
Subramaniam Ramkumar
Summary: Schwannomas and neurofibromas are the most prevalent tumors associated with cavernous hemangiomas, with only 37 documented cases of their coexistence so far. These cases are divided into conjoined association and discrete association categories, with implications for tumorigenetic molecular pathways and syndromic manifestations emphasized in previous publications.
CUREUS JOURNAL OF MEDICAL SCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Kamyar Zahedi, Sharon Barone, Marybeth Brooks, Tracy Murray Stewart, Robert A. Casero, Manoocher Soleimani
Summary: This study reveals the metabolic changes and gene expression alterations in TSC renal cystogenesis using a mouse model. The observed changes in the metabolome and transcriptome of Tsc1 KO mice are associated with unregulated cell growth and the presence of A-intercalated cells in renal cysts.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pediatrics
Andrea D. Pratico, Raffaele Falsaperla, Mattia Comella, Giuseppe Belfiore, Agata Polizzi, Martino Ruggieri
Summary: This article reports on a 5-year-old girl with a previously unreported clinical phenotype, including microcephaly, brain anomalies, intellectual disability, and growth retardation, without classical features of Tuberous Sclerosis Complex (TSC). The researchers hypothesize that this distinct phenotype may be related to a gain-of-function of the TSC1 protein product hamartin.
FRONTIERS IN PEDIATRICS
(2023)
Article
Genetics & Heredity
Zimeng Ye, Sufang Lin, Xia Zhao, Mark F. Bennett, Natasha J. Brown, Mathew Wallis, Xinyi Gao, Li Sun, Jiarui Wu, Ravikiran Vedururu, Tom Witkowski, Fiona Gardiner, Chloe Stutterd, Jing Duan, Saul A. Mullen, George McGillivray, Simon Bodek, Giulia Valente, Matthew Reagan, Yi Yao, Lin Li, Li Chen, Amber Boys, Thiuni N. Adikari, Dezhi Cao, Zhanqi Hu, Victoria Beshay, Victor W. Zhang, Samuel F. Berkovic, Ingrid E. Scheffer, Jianxiang Liao, Michael S. Hildebrand
Summary: This study investigated the contribution of low-level mosaic TSC1/TSC2 mutations in unsolved sporadic patients and families with TSC. The findings highlight the need to change laboratory practice to improve diagnostic yield.
Review
Biochemistry & Molecular Biology
Sarah J. Backe, Rebecca A. Sager, Katherine A. Meluni, Mark R. Woodford, Dimitra Bourboulia, Mehdi Mollapour
Summary: This article reviews the literature on FNIP1, FNIP2, and Tsc1 as co-chaperones and discusses their potential impact on normal cellular function and human diseases.
Article
Biochemistry & Molecular Biology
Takahiro Suzuki, Jeremy Cheret, Fernanda Dinelli Scala, Aysun Akhundlu, Jennifer Gherardini, Dana-Lee Demetrius, James D. B. O'Sullivan, Gorana Kuka Epstein, Alan J. Bauman, Constantinos Demetriades, Ralf Paus
Summary: Dysregulation of mTORC1 activity is closely related to aging, cancer, and genetic disorders. In this study, the role of mTORC1 in human hair follicles was investigated, revealing its negative regulation on hair growth and pigmentation. Inhibition of mTORC1 stimulated hair follicle growth and pigmentation, while knockdown of the TSC2 gene reduced pigmentation. These findings suggest that pharmacological inhibition of mTORC1 could be a potential strategy for managing hair loss and depigmentation disorders.
Article
Medicine, General & Internal
Marie Monaghan, Pooja Takhar, Luke Langlands, Markus Knuf, Sam Amin
Summary: Tuberous Sclerosis Complex (TSC) is a genetic condition that results in the loss of inhibition of cellular growth. Facial angiofibromas (FAs) are hamartomatous growths associated with TSC that appear as multiple small, erythematous papules on the skin of the face and may have psychosocial impacts such as anxiety and depression. A survey study found that FAs have an impact on quality of life and psychosocial well-being for TSC patients with moderate or severe FAs.
FRONTIERS IN MEDICINE
(2022)
Article
Clinical Neurology
Krzysztof Sadowski, Kamil Sijko, Dorota Domanska-Pakiela, Julita Borkowska, Dariusz Chmielewski, Agata Ulatowska, Sergiusz Jozwiak, Katarzyna Kotulska
Summary: Rapamycin can be used to treat drug-resistant epilepsy in children with TSC, and can effectively reduce the frequency of seizures at a certain dosage. The combination with vigabatrin has better efficacy.
FRONTIERS IN NEUROLOGY
(2022)
Article
Biochemistry & Molecular Biology
Martina Proietti Onori, Linda M. C. Koene, Carmen B. Schaefer, Mark Nellist, Marcel de Brito van Velze, Zhenyu Gao, Ype Elgersma, Geeske M. van Woerden
Summary: The study utilized a mouse model expressing RHEBp.P37L in the somatosensory cortex to uncover the mechanism underlying epilepsy caused by mTOR pathway hyperactivation, revealing that enhanced axonal connectivity leads to hyperexcitability in distal neurons. Blocking axonal vesicle release from RHEBp.P37L neurons alone effectively stopped seizures and normalized the hyperexcitability of distant neurons.
Article
Biochemistry & Molecular Biology
Pei-I Tsai, Chin-Hsien Lin, Chung-Han Hsieh, Amanda M. Papakyrikos, Min Joo Kim, Valerio Napolioni, Carmen Schoor, Julien Couthouis, Ruey-Meei Wu, Zbigniew K. Wszolek, Dominic Winter, Michael D. Greicius, Owen A. Ross, Xinnan Wang
Article
Immunology
James MacMurray, David E. Comings, Valerio Napolioni
BRAIN BEHAVIOR AND IMMUNITY
(2014)
Article
Immunology
Valerio Napolioni, Benjamin Ober-Reynolds, Szabolcs Szelinger, Jason J. Corneveaux, Traci Pawlowski, Sharman Ober-Reynolds, Janet Kirwan, Antonio M. Persico, Raun D. Melmed, David W. Craig, Christopher J. Smith, Matthew J. Huentelman
JOURNAL OF NEUROINFLAMMATION
(2013)
Article
Geriatrics & Gerontology
Fabio Di Pietro, Serena Dato, Francesco M. Carpi, Jason J. Corneveaux, Simona Serfaustini, Sebastiano Maoloni, Fiorenzo Mignini, Matthew J. Huentelman, Giuseppe Passarino, Valerio Napolioni
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
(2013)
Article
Neurosciences
Antonio M. Persico, Valerio Napolioni
NEUROTOXICOLOGY AND TERATOLOGY
(2013)
Article
Pharmacology & Pharmacy
Francesco M. Carpi, Silvia Vincenzetti, Jessica Ubaldi, Stefania Pucciarelli, Valeria Polzonetti, Daniela Micozzi, Fiorenzo Micinini, Valerio Napolioni
Review
Neurosciences
Michael E. Belloy, Valerio Napolioni, Michael D. Greicius
Article
Geriatrics & Gerontology
Michael E. Belloy, Sarah J. Eger, Yann Le Guen, Valerio Napolioni, Kacie D. Deters, Hyun-Sik Yang, Marzia A. Scelsi, Tenielle Porter, Sarah-Naomi James, Andrew Wong, Jonathan M. Schott, Reisa A. Sperling, Simon M. Laws, Elisabeth C. Mormino, Zihuai He, Summer S. Han, Andre Altmann, Michael D. Greicius
Summary: KL*VSHET+ reduces the risk of amyloid positivity in APOE*4 carriers but not in APOE*4 non-carriers. The combination of APOE*4 and KL*VS genotypes might enrich AD clinical trials for pre-symptomatic subjects at increased risk of developing amyloid aggregation and AD.
NEUROBIOLOGY OF AGING
(2021)
Article
Biochemical Research Methods
Marzia Antonella Scelsi, Valerio Napolioni, Michael D. Greicius, Andre Altmann
Summary: NETPAGE is an integrative approach aimed at investigating biological pathways through which rare variation results in complex disease phenotypes. Applied to AD, it enabled the identification of a set of connected genes robustly associated with case-control status, as well as correlations with conversion risk in MCI subjects. Additionally, significant enrichments in gene sets with connections to AD were discovered.
PLOS COMPUTATIONAL BIOLOGY
(2021)
Article
Oncology
Riccardo Di Fiore, Sherif Suleiman, Bridget Ellul, Sharon A. O'Toole, Charles Savona-Ventura, Ana Felix, Valerio Napolioni, Neil T. Conlon, Ilker Kahramanoglu, Miriam J. Azzopardi, Miriam Dalmas, Neville Calleja, Mark R. Brincat, Yves Muscat-Baron, Maja Sabol, Vera Dimitrievska, Angel Yordanov, Mariela Vasileva-Slaveva, Kristelle von Brockdorff, Rachel A. Micallef, Paul Kubelac, Patriciu Achimas-Cadariu, Catalin Vlad, Olga Tzortzatou, Robert Poka, Antonio Giordano, Alex Felice, Nicholas Reed, C. Simon Herrington, David Faraggi, Jean Calleja-Agius
Summary: Gynecologic tumors classified as rare face challenges in research and treatment due to scientific and technological limitations. The European Network for Gynecological Rare Cancer Research (GYNOCARE) aims to address these challenges by creating a network covering various domains from basic research to treatment. The focus is on developing new approaches to improve diagnosis and treatment for rare gynecological tumors.
Article
Genetics & Heredity
Sarah J. Eger, Yann Le Guen, Raiyan R. Khan, Jacob N. Hall, Gabriel Kennedy, Greg Zaharchuk, Julien Couthouis, William S. Brooks, Dennis Velakoulis, Valerio Napolioni, Michael E. Belloy, Clifton L. Dalgard, Elizabeth C. Mormino, Aaron D. Gitler, Michael D. Greicius
Summary: This study confirms the pathogenicity of the F386L PSEN1 variant and highlights the importance of studying families from underrepresented populations.
NEUROLOGY-GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Marilena Pariano, Matteo Puccetti, Claudia Stincardini, Valerio Napolioni, Leonardo Gatticchi, Roberta Galarini, Giorgia Renga, Carolina Barola, Marina M. Bellet, Fiorella D'Onofrio, Emilia Nunzi, Andrea Bartoli, Cinzia Antognelli, Lisa Cariani, Maria Russo, Luigi Porcaro, Carla Colombo, Fabio Majo, Vincenzina Lucidi, Enza Montemitro, Ersilia Fiscarelli, Helmut Ellemunter, Cornelia Lass-Florl, Maurizio Ricci, Claudio Costantini, Stefano Giovagnoli, Luigina Romani
Summary: Hypoxia contributes to ineffective airway inflammation in cystic fibrosis and inhibiting hypoxia-inducible factor 1 alpha (HIF-1 alpha) could impair essential immune functions. This study explores the interaction between hypoxia and the aryl hydrocarbon receptor (AhR) and demonstrates that AhR agonism can prevent hypoxia-induced inflammation and improve lung function in CF.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2023)
Article
Microbiology
Rossana Petrilli, Attilio Fabbretti, Alex Cerretani, Kathleen Pucci, Graziella Pagliaretta, Matteo Picciolini, Valerio Napolioni, Maurizio Falconi
Summary: The production of leachate, a liquid formed by rainwater percolation through waste, has led to serious problems in municipal wastewater treatment plants due to its high levels of toxic ammonia. In this study, a metagenomic approach based on next-generation sequencing was used to analyze the microbial composition of sludge in a wastewater treatment plant in Italy. Through enrichment experiments, a minimal bacterial community capable of degrading high concentrations of ammonium in leachate was identified. Further analysis revealed that certain bacterial families were responsible for ammonia oxidation and three bacteria genera were capable of nitrification coupled with denitrification. These findings provide a foundation for optimizing microorganism mixtures for the biological removal of ammonia in leachate.
Article
Cell Biology
Jhih-Rong Lin, Patrick Sin-Chan, Valerio Napolioni, Guillermo G. Torres, Joydeep Mitra, Quanwei Zhang, M. Reza Jabalameli, Zhen Wang, Nha Nguyen, Tina Gao, Matthias Laudes, Siegfried Goerg, Andre Franke, Almut Nebel, Michael D. Greicius, Gil Atzmon, Kenny Ye, Vera Gorbunova, Warren C. Ladiges, Alan R. Shuldiner, Laura J. Niedernhofer, Paul D. Robbins, Sofiya Milman, Yousin Suh, Jan Vijg, Nir Barzilai, Zhengdong D. Zhang
Summary: Extreme longevity in humans is strongly linked to genetic factors, especially rare coding variants in pathways related to insulin and AMP-activating protein kinase signaling. These rare variants may play a protective role against age-related pathology, potentially contributing to extended lifespan.
Article
Pharmacology & Pharmacy
Concetta Dagostino, Massimo Allegri, Valerio Napolioni, Simona D'Agnelli, Elena Bignami, Antonio Mutti, Ron H. N. van Schaik
PHARMACOGENOMICS & PERSONALIZED MEDICINE
(2018)