- PhD Degree in Pharmacological Sciences (University of Padova)
- Single cycle Master's degree in Chemical and Pharmaceutical Techniques, LM-13 (University of Padova)
RESEARCH, TEACHING, or OTHER INTERESTS
Pharmaceutical Science, Molecular Biology, Cellular and Molecular Neuroscience
Apoptosis and motor deficits in SPG76 hereditary spastic paraplegia: Calpain 2 inhibition as therapeutic strategy Francesca Brivio, Giulia Guarato, Elena Panzeri, Fiore Manganelli, Massimiliano Filosto, Chiara Vantaggiato, Maria Teresa Bassi Pharmacological Research, 2026 SPG76 is a complicated form of hereditary spastic paraplegia (HSP) associated with mutations in the CAPN1 gene. The encoded protein, calpain 1, is a calcium-activated cysteine protease that catalyzes the proteolytic cleavage of a variety of cellular proteins and is involved in a wide range of biological processes. Calpain 1 and calpain 2 isoforms are highly expressed in various tissues and have opposite effects on survival: calpain 1 induces the activation of Akt and ERK pro-survival pathways, regulates autophagy and is neuroprotective, while calpain 2 induces neurodegeneration. We characterized fibroblast cells derived from two SPG76 patients carrying a homozygous mutation (p.Tyr320Leufs73*) in the CAPN1 gene that leads to the absence of the protein. Loss of calpain 1 in SPG76 patient’s derived cells increased calpain 2 activation and induced autophagosome formation and accumulation, inhibited Akt and ERK1/2 pro-survival pathways, reducing GSK3β inhibition, and increased cell susceptibility to ER stress. In ER stress conditions, SPG76 cells presented unfolded protein response (UPR) activation, increased apoptosis and cell death. We analysed the potential of targeting calpain 2 and the Akt pro-survival pathway to rescue the SPG76 deranged pathways in patient’s derived cells. We found that the calpain inhibitors olesoxime and MDL28170, naringenin and the GSK3β inhibitor tideglusib were the most effective in increasing Akt activation and GSK3β inhibition and in rescuing apoptosis and cell death in SPG76 cells. Among these, olesoxime and MDL28170 reduced calpain activity, rescued apoptosis and locomotor deficits in vivo in a CalpB KO Drosophila model that replicates the SPG76 phenotype. • Loss of calpain 1 increases SPG76 cell susceptibility to ER stress • CalpB KO Drosophila model presents increased UPR activation, apoptosis and locomotor deficit • The inhibition of calpain 2 with olesoxime and MDL28170 rescues apoptosis and cell death • Olesoxime and MDL28170 increase Akt pro-survival pathway activation • Olesoxime and MDL28170 rescue locomotor deficits in vivo in the CalpB KO Drosophila model
Low, non-psychedelic doses of psilocybin as a novel treatment for MASLD, obesity and type 2 diabetes via 5-HT2B receptor-dependent mechanisms Martina Colognesi, Daniela Gabbia, Anna Signor, Miles Sarill, Lucia Centofanti, Andrea Rinaldi, Luciano Cascione, Sara Nunziata, Marco Banzato, Andrea Mattarei, Giovanna Finzi, Sonia Sonda, Diana Pendin, Ilaria Zanotto, Stefano Comai, Gianfranco Pasut, Abdullah Alajati, Miriam Saponaro, Loredana Bucciarelli, Maria Elena Lunati, Giulia Guarato, Ilaria Goggi, Stefano La Rosa, Camillo Morano, Rita Clara Paroni, Michele Dei Cas, Giuseppe Daniele, Marco Gentilucci, Marco Pappagallo, Andrea Alimonti, Paolo L. Manfredi, Franco Folli, Sara De Martin Pharmacological Research, 2026 The therapeutic potential of low, non-psychedelic doses of psilocybin, a fungal tryptamine alkaloid, was investigated in metabolic disorders including obesity, type 2 diabetes mellitus (T2DM), and liver steatosis. Mice fed a high-fat/high-fructose diet received chronic treatment with psilocybin (0.05 mg/kg) for 12 weeks. Body weight, liver histology, insulin sensitivity, and skeletal muscle function were assessed, and hepatic and muscle tissues underwent transcriptomic and lipidomic analyses. The role of three serotonin receptors (5-HT2A, 5-HT2B, and 5-HT2C) in psilocybin-induced metabolic effects was examined in human cell lines using pharmacological and CRISPR/Cas9-based genetic approaches. Low-dose psilocybin reduced body-weight gain, liver steatosis, hyperglycaemia, and insulin resistance without eliciting central nervous system effects. Multi-omics analyses revealed near-complete normalization of disrupted hepatic lipid and carbohydrate metabolism pathways. Psilocybin also improved muscle strength and function, potentially through restoration of leptin sensitivity. Mechanistic studies demonstrated that these metabolic benefits were independent of the canonical psychedelic target 5-HT2A and instead resulted from antagonism of the serotonin 5-HT2B receptor in the liver. Overall, chronic low-dose psilocybin exerts broad metabolic benefits via a hepatic 5-HT2B-dependent mechanism, distinct from its psychedelic effects, supporting its potential as a novel therapeutic strategy for liver steatosis, obesity, T2DM, and sarcopenia.
Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes Chiara Vantaggiato, Giulia Guarato, Francesca Brivio, Elena Panzeri, Beatrice Speltoni, Sentiljana Gumeni, Genny Orso, Filippo Maria Santorelli, Maria Teresa Bassi Pharmacological Research, 2025 SPG11 and SPG15 are two hereditary spastic paraplegia forms characterized by autophagosome accumulation, reduced free lysosomes and defects in autophagic lysosomal reformation (ALR). We demonstrated that attempts to rescue ALR and/or lysosome biogenesis are critical strategies for SPG15 phenotype and that SMER28 improved lysosomal reformation rescuing locomotor deficit in a SPG15 Drosophila model. Here we assessed the therapeutic potential of two FDA-approved compounds, tideglusib and naringenin, that target lysosomal function and regeneration, both registered for clinical use. Their effects were compared with those of SMER28 and of miglustat, the latter tested in a phase II clinical trial in SPG11 patients, in both SPG15 and SPG11 patient's derived cells and in the corresponding Drosophila models. We demonstrated that naringenin and SMER28 restored lysosomal and autophagic parameters in SPG15 and SPG11 cells and fly models, rescued ALR and improved locomotor deficit in vivo. Both compounds induced lysosomal tubulation, downstream of mTOR, promoting lysosomal reformation. Our work indicates that lysosomal reformation is a good strategy for herditary spastic parapegia forms with impaired lysosomal function and identifies naringenin as new modulator of this process, offering further hand to planning phase II clinical trials in SPG11-SPG15 patients.
Targeting the multifaceted neurotoxicity of Alzheimer's disease by tailored functionalisation of the curcumin scaffold Ersilia De Lorenzi, Francesca Seghetti, Andrea Tarozzi, Letizia Pruccoli, Cecilia Contardi, Massimo Serra, Alessandra Bisi, Silvia Gobbi, Giulio Vistoli, Silvia Gervasoni, Carla Argentini, Giulia Ghirardo, Giulia Guarato, Genny Orso, Federica Belluti, Rita Maria Concetta Di Martino, Morena Zusso European Journal of Medicinal Chemistry, 2023 Simultaneous modulation of multifaceted toxicity arising from neuroinflammation, oxidative stress, and mitochondrial dysfunction represents a valuable therapeutic strategy to tackle Alzheimer's disease. Among the significant hallmarks of the disorder, Aβ protein and its aggregation products are well-recognised triggers of the neurotoxic cascade. In this study, by tailored modification of the curcumin-based lead compound 1, we aimed at developing a small library of hybrid compounds targeting Aβ protein oligomerisation and the consequent neurotoxic events. Interestingly, from in vitro studies, analogues 3 and 4, bearing a substituted triazole moiety, emerged as multifunctional agents able to counteract Aβ aggregation, neuroinflammation and oxidative stress. In vivo proof-of-concept evaluations, performed in a Drosophila oxidative stress model, allowed us to identify compound 4 as a promising lead candidate.
Rescue of lysosomal function as therapeutic strategy for SPG15 hereditary spastic paraplegia Chiara Vantaggiato, Genny Orso, Giulia Guarato, Francesca Brivio, Barbara Napoli, Elena Panzeri, Simona Masotti, Filippo Maria Santorelli, Maria Lamprou, Sentiljana Gumeni, Emilio Clementi, Maria Teresa Bassi Brain, 2023 SPG15 is a hereditary spastic paraplegia subtype caused by mutations in Spastizin, a protein encoded by the ZFYVE26 gene. Spastizin is involved in autophagosome maturation and autophagic lysosome reformation and SPG15-related mutations lead to autophagic lysosome reformation defects with lysosome enlargement, free lysosome depletion and autophagosome accumulation. Symptomatic and rehabilitative treatments are the only therapy currently available for patients. Here, we targeted autophagy and lysosomes in SPG15 patient-derived cells by using a library of autophagy-modulating compounds. We identified a rose of compounds affecting intracellular calcium levels, the calcium-calpain pathway or lysosomal functions, which reduced autophagosome accumulation. The six most effective compounds were tested in vivo in a new SPG15 loss of function Drosophila model that mimicked the reported SPG15 phenotype, with autophagosome accumulation, enlarged lysosomes, reduced free lysosomes, autophagic lysosome reformation defects and locomotor deficit. These compounds, namely verapamil, Bay K8644, 2′,5′-dideoxyadenosine, trehalose, Small-Molecule Enhancer of Rapamycin 28 and trifluoperazine, improved lysosome biogenesis and function in vivo, demonstrating that lysosomes are a key pharmacological target to rescue SPG15 phenotype. Among the others, the Small-Molecule Enhancer of Rapamycin 28 was the most effective, rescuing both autophagic lysosome reformation defects and locomotor deficit, and could be considered as a potential therapeutic compound for this hereditary spastic paraplegia subtype.
Drosophila d-idua reduction mimics mucopolysaccharidosis type i disease-related phenotypes Concetta De Filippis, Barbara Napoli, Laura Rigon, Giulia Guarato, Reinhard Bauer, Rosella Tomanin, Genny Orso Cells, 2022 Deficit of the IDUA (α-L-iduronidase) enzyme causes the lysosomal storage disorder mucopolysaccharidosis type I (MPS I), a rare pediatric neurometabolic disease, due to pathological variants in the IDUA gene and is characterized by the accumulation of the undegraded mucopolysaccharides heparan sulfate and dermatan sulfate into lysosomes, with secondary cellular consequences that are still mostly unclarified. Here, we report a new fruit fly RNAi-mediated knockdown model of a IDUA homolog (D-idua) displaying a phenotype mimicking some typical molecular features of Lysosomal Storage Disorders (LSD). In this study, we showed that D-idua is a vital gene in Drosophila and that ubiquitous reduction of its expression leads to lethality during the pupal stage, when the precise degradation/synthesis of macromolecules, together with a functional autophagic pathway, are indispensable for the correct development to the adult stage. Tissue-specific analysis of the D-idua model showed an increase in the number and size of lysosomes in the brain and muscle. Moreover, the incorrect acidification of lysosomes led to dysfunctional lysosome-autophagosome fusion and the consequent block of autophagy flux. A concomitant metabolic drift of glycolysis and lipogenesis pathways was observed. After starvation, D-idua larvae showed a quite complete rescue of both autophagy/lysosome phenotypes and metabolic alterations. Metabolism and autophagy are strictly interconnected vital processes that contribute to maintain homeostatic control of energy balance, and little is known about this regulation in LSDs. Our results provide new starting points for future investigations on the disease’s pathogenic mechanisms and possible pharmacological manipulations.
