Oxidative Stress and Friedreich’s Ataxia

Friedreich’s Ataxia (FRDA) is a neurodegenerative disorder caused by a deficiency of the protein frataxin and characterized by oxidative stress. The first aim of my research project was to analyze the effects of tocotrienol in FRDA patients. Patients received for 2 months a low dose of tocotrienol. A number of biochemical parameters related to oxidative stress were studied. We consistently showed that taking for 2 months a low dose of tocotrienol led to the decrease of oxidative stress indexes in FRDA patients. Also, this study provides a suitable model to investigate the efficacy of natural compounds to counteract the oxidative stress in FRDA. Furthermore, we investigated whether the tocotrienol was able to modulate the expression of the frataxin isoforms (FXN-1, FXN -2, FXN-3) in FRDA patients. We demonstrated that tocotrienol leads to a specific and significant increase of FXN-3 expression. As no structural and functional details were available for FNX-2 and FXN-3, 3D-models were built. FXN-1, the canonical isoform, was then docked on the human iron-sulphur complex and functional interactions were computed; when FXN-1 was replaced by FXN-2 or FNX-3, we found that the interactions were maintained, thus suggesting a possible biological role for both isoforms. The second aim of my research project was to investigate the role of a single nucleotide polymorphism (SNP) in the protein Sirtuin 6 in FRDA patients. In fact, it was known that those who harbour a SNP (Asn46/Ser46) in the gene enconding Sirt6 show a better outcome those individuals who are homozygous for the Asn 46 allele. We found that fibroblasts and iPSC-derived neurons from FRDA patients harboring the SNP (Asn46/Ser46) have a reduced amount of Sirt6 protein compared to cells from individuals who are homozygous for the prevalent Asn allele. Our studies provide new information on the role of Sirtuins in FRDA pathogenesis.

Secondary Microseisms Characterization and Green’s Function Extraction at the Larderello-Travale Geothermal Field (Italy)

Over the past ten years, the cross-correlation of long-time series of ambient seismic noise (ASN) has been widely adopted to extract the surface-wave part of the Green’s Functions (GF). This stochastic procedure relies on the assumption that ASN wave-field is diffuse and stationary. At frequencies <1Hz, the ASN is mainly composed by surface-waves, whose origin is attributed to the sea-wave climate. Consequently, marked directional properties may be observed, which call for accurate investigation about location and temporal evolution of the ASN-sources before attempting any GF retrieval. Within this general context, this thesis is aimed at a thorough investigation about feasibility and robustness of the noise-based methods toward the imaging of complex geological structures at the local (∼10-50km) scale. The study focused on the analysis of an extended (11 months) seismological data set collected at the Larderello-Travale geothermal field (Italy), an area for which the underground geological structures are well-constrained thanks to decades of geothermal exploration. Focusing on the secondary microseism band (SM;f>0.1Hz), I first investigate the spectral features and the kinematic properties of the noise wavefield using beamforming analysis, highlighting a marked variability with time and frequency. For the 0.1-0.3Hz frequency band and during Spring- Summer-time, the SMs waves propagate with high apparent velocities and from well-defined directions, likely associated with ocean-storms in the south- ern hemisphere. Conversely, at frequencies >0.3Hz the distribution of back- azimuths is more scattered, thus indicating that this frequency-band is the most appropriate for the application of stochastic techniques. For this latter frequency interval, I tested two correlation-based methods, acting in the time (NCF) and frequency (modified-SPAC) domains, respectively yielding esti- mates of the group- and phase-velocity dispersions. Velocity data provided by the two methods are markedly discordant; comparison with independent geological and geophysical constraints suggests that NCF results are more robust and reliable.