Biggio, Maria Luigia (2018) Danno ossidativo ed aggregati proteici nella Sclerosi Laterale Amiotrofica: possibili target diagnostici e terapeutici. Doctoral Thesis.
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Aim: Riluzole is the only available cure for ALS, with limited effects for patients and diagnosis is based only on exclusion criteria for other diseases. Oxidative stress and misfolded proteins aggregation play a main role in ALS pathogenesis. We would propose Cerium oxide nanoparticles (CeONPs) as pharmacological adjuvant in Riluzole treatment and VAPB protein as new non-invasive targets for an early diagnosis.
Methods: PBMC and fibroblasts were isolated from ALS and Parkinson’s patients and healthy controls. CeONPs were added in murine hSOD1wt/G93A NSC-34 and human fibroblasts and H2O2 100µM was used to induce oxidative stress. CeONPs effects on cell survival, mitochondrial activities, oxidative stress and misfolded proteins aggregates were evaluated. Meantime PBMC were used to evaluate aggregates presence and markers of apoptosis and oxidative stress were evaluated.
Results: We identified optimal CeONPs concentration that induces a slightly protective effect on oxidative damage in both human fibroblasts and murine cells. As regard VAPB, we identified a high presence of VAPB aggregates in ALS patients respect to healthy controls and a substantial re-organization and re-distribution of ER. Cell VAPBwt/P56S cultures revealed high levels of oxidative stress markers and ubiquitinated proteins.
Conclusions: Preliminary results confirm that protein aggregates and oxidative stress could be markers for early and more specific diagnosis for ALS. Moreover, CeONPs treatment could open perspective to its used as pharmacological adjuvant for Riluzole therapy. Further experiments are needed to confirm our data.
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