Seminars



α1-antitrypsin deficiency and the serpinopathies – pathological polymers and treatment with small molecules
11/03/2024 h 16:00 Room C1 Pharmacology Building CU024
α1-antitrypsin is the most abundant circulating proteinase inhibitor. Severe deficiency typically results from homozygous inheritance of the Z allele (Glu342Lys). We showed over 30 years ago that the Z allele caused α1-antitrypsin to undergo a conformational transition to form chains of ordered polymers that are retained as inclusions within hepatocytes in association with liver disease and cirrhosis. We subsequently showed that many mutations caused α1-antitrypsin to polymerise and that there was a genotype-phenotype relationship between the severity of the mutation and the severity of both the plasma deficiency of α1- antitrypsin and liver disease, that we can explain by the rate of polymer formation. The same process of polymerisation occurs in mutants of other serine proteinase inhibitors (serpins), most notably neuroserpin in association with neuronal inclusions that underlie dementia and epilepsy. The challenge has been to define the structure of the pathological polymer that forms in vivo. Three models have been proposed with our current data supporting the C-sheet model for polymers of Z α1-antitrypsin. The results allow the rational design of novel small molecules that can block polymer formation and so ameliorate disease, whether it be the liver disease secondary to mutations in α1-antitrypsin or dementia secondary to mutants of neuroserpin. Different mutations may require different small molecules. The proof-principle of this approach is our development of orally bioavailable small molecules with GSK, and now BioMarin, that bind preferentially to Z α1-antitrypsin, block polymerisation and reverse liver disease in transgenic mice. These molecules are now in clinical trials.
NATURAL INOSITOLS AND ALZHEIMER’S DISEASE: AN UNEXPECTED SUPPORTIVE THERAPY FOR TAUOPATHIES
09/10/2023

Developmental wiring and adult plasticity of neural circuits
Friday March 25th 2022 h 11:00

Novel Roles of Progranulin in Lysosomes: Implications for FTD and Therapeutics
February 11th 2022 h 16.00

Mechanisms of memory impairment and strategies of neuroprotection in Alzheimer’s disease (Webinar)
Friday April 9th 2021 04:30 p.m. CET

Sexual differentiation of the brain as a risk factor in the development of autism-related behaviors (Webinar)
Friday March 19th, 2021 4.00 pm

Gruppo Servier in Italia: figure professionali e prospettive di inserimento
Venerdi’ 5 marzo 2021, ore 10-12

Psychedelics: Brain Mechanisms
March 18th 3:00 p.m.

Functional And Regional Heterogeneity Of Enteric Glia In The Enteric Nervous System: Pathophysiological and Pharmacological implications in health and disease
20/01/23
by Dr. Luisa Seguella Dipartimento di Fisiologia e Farmacologia, Università Sapienza di Roma
3rd UNICA STUDENT WEBINAR ON “PHARMA AND BIOMEDICAL CAREERS IN EUROPE
Monday 25 January 2021, 10 am CET

© Università degli Studi di Roma "La Sapienza" - Piazzale Aldo Moro 5, 00185 Roma