Prof. Pierfausto Seneci
Università degli Studi di Milano, Milan, Lombardy, Italy
'%3e%3cpath%20d='M22.1642%2019.0924C21.7317%2018.068%2021.1041%2017.1375%2020.3163%2016.3527C19.5309%2015.5656%2018.6006%2014.9381%2017.5766%2014.5048C17.5674%2014.5002%2017.5582%2014.4979%2017.5491%2014.4933C18.9774%2013.4616%2019.9059%2011.7811%2019.9059%209.88504C19.9059%206.74408%2017.3611%204.19922%2014.2201%204.19922C11.0792%204.19922%208.53429%206.74408%208.53429%209.88504C8.53429%2011.7811%209.46282%2013.4616%2010.8912%2014.4956C10.882%2014.5002%2010.8728%2014.5025%2010.8636%2014.5071C9.83652%2014.9404%208.91487%2015.5617%208.1239%2016.355C7.33685%2017.1404%206.70933%2018.0707%206.276%2019.0947C5.85031%2020.0972%205.62072%2021.172%205.59967%2022.2609C5.59905%2022.2853%205.60335%2022.3097%205.61229%2022.3325C5.62123%2022.3553%205.63465%2022.376%205.65174%2022.3935C5.66883%2022.4111%205.68926%2022.425%205.71182%2022.4345C5.73437%2022.444%205.7586%2022.4489%205.78308%2022.4489H7.15868C7.25956%2022.4489%207.3398%2022.3686%207.3421%2022.2701C7.38795%2020.5001%208.09868%2018.8425%209.35506%2017.5861C10.655%2016.2862%2012.3814%2015.5709%2014.2201%2015.5709C16.0588%2015.5709%2017.7852%2016.2862%2019.0852%2017.5861C20.3415%2018.8425%2021.0523%2020.5001%2021.0981%2022.2701C21.1004%2022.3709%2021.1807%2022.4489%2021.2815%2022.4489H22.6571C22.6816%2022.4489%2022.7058%2022.444%2022.7284%2022.4345C22.751%2022.425%2022.7714%2022.4111%2022.7885%2022.3935C22.8056%2022.376%2022.819%2022.3553%2022.8279%2022.3325C22.8369%2022.3097%2022.8412%2022.2853%2022.8406%2022.2609C22.8176%2021.165%2022.5907%2020.0989%2022.1642%2019.0924ZM14.2201%2013.8284C13.1678%2013.8284%2012.1773%2013.418%2011.4322%2012.6729C10.6871%2011.9278%2010.2767%2010.9374%2010.2767%209.88504C10.2767%208.83271%2010.6871%207.84227%2011.4322%207.09715C12.1773%206.35204%2013.1678%205.94165%2014.2201%205.94165C15.2724%205.94165%2016.2629%206.35204%2017.008%207.09715C17.7531%207.84227%2018.1635%208.83271%2018.1635%209.88504C18.1635%2010.9374%2017.7531%2011.9278%2017.008%2012.6729C16.2629%2013.418%2015.2724%2013.8284%2014.2201%2013.8284Z'%20fill='%238590A2'/%3e%3c/g%3e%3c/svg%3e)
Co-authors
Following
Followers
Research Focus & Metrics
Explore full metrics on Scilit
Academic Career Length
42Years (1985-Present)
(Calculated once Scilit publication data is synced: current year − year of first publication + 1)
Representative Publications
View All Publications20 June 2006 in Proceedings of the National Academy of Sciences
Journal Article
SCSylvie Le Corre
Sylvie Le Corre
HKHans W. Klafki
Hans W. Klafki
NPNikolaus Plesnila
Nikolaus Plesnila
GHGabriele Hübinger
Gabriele Hübinger
AOAxel Obermeier
Axel Obermeier
HRHanno M. Roder
Hanno M. Roder
+10
An orally bioavailable and blood–brain barrier penetrating analog of the kinase inhibitor K252a was able to prevent the typical motor deficits in the tau (P301L) transgenic mouse model (JNPL3) and markedly reduce soluble aggregated hyperphosphorylated tau. However, neurofibrillary tangle counts were not reduced in the successfully treated cohort, suggesting that the main cytotoxic effects of tau are not exerted by neurofibrillary tangles but by lower molecular mass aggregates of tau. Our findings strongly suggest that abnormal tau hyperphosphorylation plays a critical role in the development of tauopathy and suggest a previously undescribed treatment strategy for neurodegenerative diseases involving tau pathology.
10 November 2015 in Scientific Reports
Journal Article
VDVito Giuseppe D’aGostino
Vito Giuseppe D’aGostino
PLPreet Lal
Preet Lal
BMBarbara Mantelli
Barbara MantelliCTChristopher Tiedje
Christopher TiedjeCZChiara Zucal
Chiara ZucalAPAlessandro Provenzani
Alessandro Provenzani +6
Post-transcriptional regulation is an essential determinant of gene expression programs in physiological and pathological conditions. HuR is a RNA-binding protein that orchestrates the stabilization and translation of mRNAs, critical in inflammation and tumor progression, including tumor necrosis factor-alpha (TNF). We identified the low molecular weight compound 15,16-dihydrotanshinone-I (DHTS), well known in traditional Chinese medicine practice, through a validated high throughput screening on a set of anti-inflammatory agents for its ability to prevent HuR:RNA complex formation. We found that DHTS interferes with the association step between HuR and the RNA with an equilibrium dissociation constant in the nanomolar rangein vitro(Ki = 3.74 ± 1.63 nM). In breast cancer cell lines, short term exposure to DHTS influences mRNA stability and translational efficiency of TNF in a HuR-dependent manner and also other functional readouts of its post-transcriptional control, such as the stability of selected pre-mRNAs. Importantly, we show that migration and sensitivity of breast cancer cells to DHTS are modulated by HuR expression, indicating that HuR is among the preferential intracellular targets of DHTS. Here, we disclose a previously unrecognized molecular mechanism exerted by DHTS, opening new perspectives to therapeutically target the HuR mediated, post-transcriptional control in inflammation and cancer cells.
18 July 2017 in Nucleic Acids Research
Journal Article
PLPreet Lal
Preet Lal
Linda CerofoliniVDVito Giuseppe D’aGostino
Vito Giuseppe D’aGostino
CZChiara Zucal
Chiara ZucalCFCarmelo Fuccio
Carmelo Fuccio
APAlessandro Provenzani
Alessandro Provenzani +22
The Human antigen R protein (HuR) is an RNA-binding protein that recognizes U/AU-rich elements in diverse RNAs through two RNA-recognition motifs, RRM1 and RRM2, and post-transcriptionally regulates the fate of target RNAs. The natural product dihydrotanshinone-I (DHTS) prevents the association of HuR and target RNAs in vitro and in cultured cells by interfering with the binding of HuR to RNA. Here, we report the structural determinants of the interaction between DHTS and HuR and the impact of DHTS on HuR binding to target mRNAs transcriptome-wide. NMR titration and Molecular Dynamics simulation identified the residues within RRM1 and RRM2 responsible for the interaction between DHTS and HuR. RNA Electromobility Shifts and Alpha Screen Assays showed that DHTS interacts with HuR through the same binding regions as target RNAs, stabilizing HuR in a locked conformation that hampers RNA binding competitively. HuR ribonucleoprotein immunoprecipitation followed by microarray (RIP-chip) analysis showed that DHTS treatment of HeLa cells paradoxically enriched HuR binding to mRNAs with longer 3′UTR and with higher density of U/AU-rich elements, suggesting that DHTS inhibits the association of HuR to weaker target mRNAs. In vivo, DHTS potently inhibited xenograft tumor growth in a HuR-dependent model without systemic toxicity.
31 July 2020 in Nature Communications
Journal Article
LMLuca Muzio
Luca MuzioRSRiccardo Sirtori
Riccardo Sirtori
DGDavide Gornati
Davide Gornati
SESimona Eleuteri
Simona Eleuteri
AFAndrea Fossaghi
Andrea Fossaghi
GMGianvito Martino
Gianvito Martino +13
Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.
11 May 2010 in British Journal of Cancer
Journal Article
DLDaniele Lecis
Daniele LecisCDC Drago
C Drago
LML Manzoni
L ManzoniPierfausto SeneciCSC Scolastico
C Scolastico
DDD Delia
D Delia +5
Background: Methods: Results: Conclusion:
22 March 1993 in FEBS Letters
Journal Article
ESEdoardo Sarubbi
Edoardo Sarubbi
Pierfausto SeneciMAMichael R. Angelastro
Michael R. Angelastro
NPNorton P. Peet
Norton P. Peet
MDMaurizio Denaro
Maurizio Denaro
KIKhalid Islam
Khalid Islam
About Me
Pierfausto Seneci received a degree in Chemistry in Pavia, in 1983, and was then a postdoc at Politecnico di Milano. In 1986, he joined Lepetit (Gerenzano, I), working on natural products. In 1992, he joined Marion Merrell Dow (Strasbourg, F), working on neurodegenerative diseases. In 1995, he joined Selectide (Tucson, Arizona), synthesizing natural-product-like libraries. In 1996, he joined SmithKlineBeecham (Rennes, F) as Head of Medicinal Chemistry, working in oncology and osteoporosis. In 1997, he joined GlaxoWellcome (Verona, I) as Director of Lead Discovery, responsible for antibacterial and CNS projects.
In 2000, he was a Founder of biotech NADAG (Munich, D), where he led efforts to cure Alzheimer's disease; in 2003, he became the CEO, and he merged NADAG with Sireen AG to give Sirenade Pharma, securing financing and licensing in CNS/neurodegeneration.
In late 2002, he became an Associate Professor at the University of Milan, where he taught basic and advanced courses, and led projects in CNS and oncology. Since 2005, he has assisted Italian and European companies as a business development–strategic consultant.
Between 1997 and 2009, he was a Scientific Advisor for UNIDO, to facilitate technology transfer to developing countries. Since 2009, he has acted as an expert to evaluate projects and companies for the EC, the “Regione Lazio”, “Regione Puglia”, “Regione Sardegna” and MIUR-Italy. He is the author of four books, more than 120 scientific papers, and 15 patents.