Biology subjects

Di Fonzo, A.

Publications and source records attributed to Di Fonzo, A..

2 recordsLinked to original sources

bioRxiv2025

A microRNA-based Therapy against Human Medulloblastoma Validated in a Xenotransplant Model using Wild-Type Mouse Embryos

Medulloblastoma (MB) is the most prevalent malignant pediatric brain tumor. Its poor prognosis is driven by therapy-resistant cancer stem-like cells (CSCs), which are challenging to study in traditional preclinical models. MicroRNAs (miRNAs) modulate tumor-related pathways by repressing oncogenic gene expression, a function lost in cancer. We assessed the therapeutic potential of miRNA restoration in human MB from distinct subgroups, validated in a xenotransplant model using wild-type (WT) mouse embryos. Multi-omics, imaging, and in silico analyses were employed to identify underlying mechanisms and therapeutic targets. Human MB cells formed tumors in embryonic mouse brains that mirrored key MB features, including vascularized CSC niches and metastases. Restoration of underexpressed miRNAs reduced tumor growth and invasiveness in vitro and in vivo. These miRNAs synergistically repressed gene networks related to cell adhesion and RNA metabolism, shared oncogenic pathways across MB subgroups. Our embryonic xenotransplant model provides a clinically relevant platform for evaluating next-generation gene therapies in pediatric brain cancer.

cancer biology↗

bioRxiv2021

The activities of LRRK2 and GCase are positively correlated in clinical biospecimens and experimental models of Parkinson's disease

LRRK2 is a kinase involved in different cellular functions, including autophagy, endolysosomal pathways and vesicle trafficking. Mutations in LRRK2 cause autosomal dominant forms of Parkinsons disease (PD). Heterozygous mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), are the most common genetic risk factors for PD. Moreover, GCase function is altered in idiopathic PD and in other genetic forms of the disease. Recent work suggests that LRRK2 kinase activity can regulate GCase function. However, both a positive and a negative correlation have been described. To gain insights into the impact of LRRK2 on GCase, we investigated GCase levels and activity in LRRK2 G2019S knockin mice, in clinical biospecimens from PD patients carrying this mutation and in patient-derived cellular models. In these models we found a positive correlation between the activities of LRRK2 and GCase, which was further confirmed in cell lines with genetic and pharmacological manipulation of LRRK2 kinase activity. Overall, our study indicates that LRRK2 kinase activity affects both the levels and the catalytic activity of GCase.

neuroscience↗