PRIN 2022 Scorrimento -  Prot. 2022XTSLAP

Many neurodegenerative diseases exhibit abnormal morphology and biochemical dysfunction of mitochondria. In Alzheimer's, Parkinson's, Huntington's diseases and amyotrophic lateral sclerosis, the role of mitochondria in neurodegeneration has been established, supporting the hypothesis that mitochondrial impairment has a critical role in the neurodegenerative process. Fragile X-related Disorders (FXDs) are a group of clinical conditions that primarily result from the CGG expansion at the 5’UTR of the FMR1 gene. Premutation (PM, 56-200 CGGs) carriers present a risk for a neurodegenerative condition named Fragile X-associated Tremor/Ataxia Syndrome (FXTAS, OMIM#300623). Full mutation (FM, >200 CGGs) alleles become methylated, resulting in FMR1 silencing and hence in Fragile X syndrome (FXS, OMIM#300624), a neurodevelopmental disorder affecting learning and behaviour. There exist rare alleles with a FM completely unmethylated (UFM), thus preventing to develop FXS. The FMRP protein, which is absent in FXS and downregulated in PM and UFM, is an RNA-binding protein involved in several aspects of RNA metabolism particularly in brain. Pharmacological approaches based on promising targets failed to show significant clinical benefits illustrating the need of novel therapies. Recent data indicate that mitochondrial function is deranged in FXDs. We found high levels of the superoxide dismutase 2 enzyme, associated with atypical mitochondrial morphology, in PM and UFM cells and published these results thanks to our previous PRIN project (Prot. 201789LFKB). Our data show that mitochondrial proteins involved in OXPHOS and the cyclophilin D (CypD), a known modulator of the permeability transition pore (PTP) inducing apoptosis, are upregulated in fibroblasts derived from FXS, PM and UFM patients. These findings are confirmed in preliminary data in iPSCs derived-neurons, suggesting that fibroblasts recapitulate neuronal phenotypes. Although the molecular identity of the PTP is still under debate, CypD is widely accepted as its positive regulator. It has been therefore suggested as a target in mitochondrial-related diseases, but its role in FXDs has not been investigated so far. CypD has been proposed to interact with the OSCP subunit of ATP synthase and several displacing-compounds are available, although the molecular determinants of this interaction remain unclear and need further investigation.

Our project aims at clarifying the mitochondrial mechanisms involved in the pathophysiology of FXDs to develop novel treatments as follows: 1) to explore the molecular mechanisms causing mitochondrial dysfunction in FXD- fibroblasts; 2) to select targeted compounds able to ameliorate mitochondrial phenotype in FXD- fibroblasts; 3) to explore the mitochondrial function after treatment of FXD- fibroblasts with selected compounds at the molecular and proteomic level; 4) to validate and restore dysregulated pathways identified in fibroblasts using iPSCs derived neurons.

Working group:

• Elisabetta Tabolacci - Responsabile scientifico UCSC
• Eugenio Sangiorgi

Partners:

• Università degli Studi di Bologna
• Università degli Studi di Padova
• Saint Camillus International University of Health Sciences (UniCamillus)