Institute of Crystallography - CNR

Study of the role of oxidative stress in the onset of neurodegenerative diseases

Studies at the molecular level have highlighted the multifactoriality of chronic-degenerative diseases, to whose onset the following contribute: chronic inflammatory state, genome instability, excessive ROS production, alterations in morphology and mitochondrial function and epigenetic alterations.

The model cell system that we use in our laboratory is primary and/or transformed fibroblasts from patients with Cockayne syndrome, a rare disease characterized by a neurodegenerative phenotype and premature aging. We have shown that Cockayne syndrome fibroblasts present mitochondrial dysfunction with membrane depolarization and alteration of mitochondrial morphology, alterations in the mitophagic process and increase in ROS with consequent increase in oxidative damage to nuclear DNA. By over-expressing Parkin (mitophagy protein) or by inhibiting Drp1 (mitochondrial fission protein) we were able to reverse the dysfunctional mitochondrial phenotype.
Mitochondrial dysfunction characterizes various neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, therefore we aim to characterize, in different cell types, mitochondrial dysfunction by analyzing gene and protein expression, as well as post-translational modifications of proteins involved in the mitochondrial dynamics process.
Furthermore, in order to broaden the range of biomarkers that can be used in future population studies, we are developing quantitative amplification techniques to analyze both nuclear and mitochondrial DNA damage, measuring deletions and oxidized guanine levels.
Our aim is therefore, through an integrated approach, to further characterize the alterations at the mechanistic level underlying neurodegenerative diseases and to identify potential new biomarkers, both predictive and therapeutic.

Reference works

– Overexpression of parkin rescues the defective mitochondrial phenotype and the increased apoptosis of Cockayne Syndrome A cells, Pascucci B, D’Errico M, Romagnoli A, De Nuccio C, Savino M, Pietraforte D, Lanzafame M, Calcagnile AS, Fortini P, Baccarini S, Orioli D, Degan P, Visentin S, Stefanini M, Isidoro C, Fimia GM, Dogliotti E. Oncotarget 8(61):102852-67, 2016
– Oxygen-Dependent Accumulation of Purine DNA Lesions in Cockayne Syndrome Cells. Krokidis MG, D’Errico M, Pascucci B, Parlanti E, Masi A, Ferreri C, Chatgilialoglu C.
Cells 9: 1671, 2020
– The interplay between mitochondrial functionality and genome integrity in the prevention of human neurologic diseases D’Errico M, Parlanti E, Pascucci B, Filomeni G, Mastroberardino PG, Dogliotti E.
Arch Biochem Biophys., 710:108977, 2021
– DRP1 Inhibition Rescues Mitochondrial Integrity and Excessive Apoptosis in CS-A Disease Cell ModelsPascucci B, Spadaro F, Pietraforte D, De Nuccio C, Visentin S, Giglio P, Dogliotti E and D’Errico M. International Journal of Molecular Sciences, 22(13):7123, 2021

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