Claudia Bagni - Selected Publications#
PUBLICATIONS (in reverse chronological order):
1) Mariano V., Kanellopoulos A., Ricci C., Di Marino D., C. Borrie S., Dupraz S., Bradke F., Achsel T., Legius E., Odent S., Billuart P., Bienvenu T. and Bagni C. (2023). Intellectual Disability and Behavioral Deficits Linked to CYFIP1 Missense Variants Disrupting Actin Polymerization. Biol. Psychiatry, S0006-3223(23)01563-9. (I.F. 12.81).
prof. Bagni team employed a multidisciplinary approach to investigate a family with members exhibiting intellectual disability, autism spectrum disorder, spastic tetraparesis, epileptic encephalopathy, and brain morphology defects. Bi-allelic missense point mutations in the CYFIP1 gene, located in the protein domain responsible for WRC interactions, were identified. Utilizing patients skin fibroblasts, molecular modeling, cell biology, and genetic/Drosophila tools, the team unveiled the molecular mechanisms behind this complex clinical phenotype, emphasizing CYFIP1 role in actin-mediated brain developmental processes. This study underscores the significance of using Drosophila as a model system to study human diseases and provides insights into CYFIP1 association with ASD and deficits in brain development. This study enhances our comprehension of the mechanisms impacted by Cyfip1 haploinsufficiency, a factor in the 15q11.2 microdeletion syndrome. This syndrome is linked to intellectual disability (ID), schizophrenia, and autism.
2) Pedini G., Chen Ch-L., Achsel T. and Bagni C. (2023) Cancer drug repurposing in autism spectrum disorder. Trends in Pharmacol. Sciences 12: 963-977. (I.F. 17.638).
Growing evidence suggest that cancer and neurodevelopmental disorders – two diseases apparently unrelated – share common pathways. This congruence in pathways advocates for a more profound exploration, seeking untapped therapeutic avenues to identify effective treatments for ASD. Here prof. Bagni and her team have synthetically reviewed the emerging field of repurposing cancer compounds in neuroscience, specifically in the context of ASD and related disorders providing new insights and food for thoughts.
3) Mercaldo V, Vidimova B, Gastaldo D, Fernández E, Lo Adrian C, Cencelli G, Pedini G, De Rubeis S, Longo F, Klann E, Smit A.B., Grant S.G.N., Achsel T. and Bagni C. (2023). Altered striatal actin dynamics drives behavioral inflexibility in a mouse of Fragile X syndrome. Neuron 11: 1760-1775.e8. (I.F. 18.688).
In this manuscript prof. Bagni and her team discovered an altered behavioral flexibility in the dorsal striatum in FXS. Of note, they identified changes in the actin-cytoskeleton composition at the striatal postsynaptic density, leading to reduced synaptic actin-dynamics, lower striatal spine density, and altered spine morphology, exacerbating inflexibility and perseverative behaviors in vivo. Enhanced striatal actin-dynamics improved FXS behavioral deficits. Her findings, using a multidisciplinary approach, highlight striatal actin-dynamics as a crucial regulator of behavioral flexibility, emphasizing the striatum significance in core deficits observed in FXS and autism spectrum disorders, with potential implications for other neurological diseases.
4) Cencelli G., Pacini L., De Luca A., Messia I., Kang Y., Nobile V., Tabolacci E., Jin P., Farace MG., and Bagni C (2023). Age-dependent dysregulation of APP in brain and skin cells from Fragile X individuals. Cells, 12(5):758. (I.F. 6.0).
Based on a seminal work on APP by prof. Bagni and her team published in Neuron in 2015, in this study, the researchers explored APP metabolism in human FXS fibroblasts, stem cells, and organoids. They observed a developmental-dependent dysregulation of APP metabolism, specifically detecting APP dysregulation in FXS fibroblasts from young individuals, iPSCs-derived neural precursor cells, and early-stage forebrain organoids. Furthermore, the use of a specific peptide targeting APP processing, leading to a decrease in sAPPα levels, rescued a molecular defect in FXS cells. This study, for the first time, identifies such dysregulation in human cells with a neuronal fate and underscores its developmental implications, which have not been considered in prior clinical trial designs.
5) Mariano V, Kanellopoulos Alexandros K., Aiello Giuseppe, Lo Adrian C., Legius E, Achsel T and Bagni C (2023). SREBP modulates the NADP+/NADPH cycle to control night sleep in Drosophila. Nat. Commun. 14(1):763. (I.F. 17.7).
The incidence of sleep disturbance is higher in children with ASD compared to typically developing individuals (up to 85%). Prof. Bagni and her team, using Drosophila melanogaster, identified a molecular mechanism that regulates sleep homeostasis and links a sleep disturbance to metabolic disorders. They describe for the first time how an impairment in the activity of two important key metabolic regulators, i.e. the sterol regulatory element binding protein SREBP and the Malic enzyme in the brain, contribute to sleep deficits. These findings might have an implication for human health because in human, the gene SREBF1 has been associated with chronic insufficient sleep, genome-wide association studies classified human SREBF1 as risk factor for schizophrenia, and transcription binding sites of genes recognized by SREBP1 are enriched in single nucleotide variants associated to ASD. In addition, alterations in NADP+/NADPH levels are observed in children with ASD.
6) Pedini G, Buccarelli MC, Bianchi F, Pacini L, Cencelli G1, D'Alessandris QG, Martini M, Giannetti S, Sasso F, Melocchi V, Farace MG, Achsel T, Larocca LM, Ricci-Vitiani L, Pallini R, Bagni C (2022). FMRP modulates the Wnt signalling pathway in glioblastoma. Cell Death Dis. 8:719. (I.F. 9.696).
This work by prof. Bagni and her team suggests that lack of the protein FMRP may play a protective role against the growth and progression of this aggressive tumour. Elevated FMRP levels are directly linked to poor glioblastoma patient survival. Modulating FMRP levels in GSCs reduces their proliferative activity and diminishes their ability to generate highly proliferative and invasive tumors when transplanted into mouse brains. This study contributes to understanding the intricate network between RBPs and cancer-related RNA targets in the context of glioblastoma, providing the first identification and validation of FMRP-associated mRNAs in glioma stem cells. The findings impact intellectual disabilities and cancer, explaining molecularly how reduced or absent FMRP protects against tumor growth. Given the unmet medical need for glioblastoma, FMRP's influence on glioblastoma progression suggests it could serve as a future marker for tumor aggressiveness.
7) Lo A.C., Rajan N., Gastaldo D., Telley L., Hilal M.L., Buzzi A., Simonato M., Achsel T., Bagni C. (2021). Absence of RNA-binding protein FXR2P prevents prolonged phase of kainate-induced seizures. EMBO Reports 109, 1-10. (I.F. 9.421).
Here prof. Bagni and her team using a mouse model for the Fragile X related Protein 2, discovered that the absence of this RNA binding protein leads to a protective effect towards a status epilepticus caused specifically by kainic acid. They identified the FXR2P regulon and found that several of the gene targets are associated with the glutamatergic signaling. With this work they show for the first time a new function for FXR2P providing the scientific community with a great potential for a deeper understanding of epilepsy.
8) Kanellopoulos A.K., Mariano V, Spinazzi M, Jae Woo Y, McLean C, Pech U, Li KW, Armstrong J.D., A, Callaerts P, Smit A.B., Abrahams B.S., Fiala A, Achsel T and Bagni C (2020). Aralar sequesters GABA into hyperactive mitochondria causing social behavior deficits. Cell, 6: 1178-1197.e20. (I.F. 66.850).
prof. Bagni and her team made seminal contributions to our understanding of the mechanisms affected in the context of the Cyfip1 haploinsufficiency. In this study thery discovered that in Drosophila, Cyfip1 heterozygosity causes, through the dysregulation of multiple proteins, a hyperactivity of mitochondria, specifically in the brain. The latter finding led to the elucidation of a novel mechanism, by which mitochondria regulate inhibitory neurotransmission: increased mitochondrial activity and their subsequent hyperpolarization drives the transporter Aralar boosting the sequestration of GABA into the mitochondria, thereby dampening GABA availability, and affecting social behavior. Social deficits are rescued by modulation of GABA levels and mitochondrial activity. Of note, these findings have been patented at the University of Lausanne.
This works was highlighted in Signal Transduct Target Ther (2020) 5:126
9) Domínguez-Iturza N, Lo A.C., Shah D, Armendáriz M, Vannelli A1, Mercaldo V, Trusel M, Li K.W., Gastaldo D., Santos AR, Callaerts-Vegh Z, D’Hooge R, Mameli M, Van der Linden A, Smit A.B, Achsel T and Bagni C (2019). The autism and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour. Nat. Commun., 10: 3454. (I.F. 17.7).
prof. Bagni and her team with this work they generated the first evidence that CYFIP1 affects brain wiring and functional connectivity, giving therefore a possible explanation why CYFIP1 deficiency in 15q11.2 patients leads to complex neuropsychiatric disorders. Furthermore their data show that the Cyfip1 heterozygote mouse has ASD and SCZ-like behaviours and therefore it has face validity for the BP1-BP2 deletion syndrome.
This work was also highlighted in Nat. Rev. Neurosci., (2019) 20: 575 and in Trends Neurosci. (2019) 42: 843-844
10) Rosina E, Battan B, Siracusano M, Di Criscio L, Hollis F, Pacini L, Curatolo P, Bagni C (2019). Disruption of mTOR and MAPK pathways correlates with severity in idiopathic autism. Transl. Psychiatry. 9(1):50. (I.F. 7.989).
prof. Bagni and her team, in collaboration with clinicins, conducted a study characterizing the clinical and molecular phenotypes of individuals with mild or severe Autism Spectrum Disorders (ASDs). Examination of peripheral blood in patients revealed elevated mTOR and MAPK signaling pathways. Crucially, these molecular variances correlated with the clinical severity of ASD, indicating that distinct components of the protein synthesis pathway may influence the severity of ASDs.
