In this work we present a detailed analysis of the dual role of lysosomes and lysosomal cathepsins in the two main pathways of cell death, namely, apoptosis and autophagy. Destabilization of the lysosomal membranes by lysosomotropic detergents seems to be a promising strategy as it would not only disable autophagy, but also promote apoptosis through the initiation of the lysosomal pathway. On the other side, the impaired autophagy and lysosomal degradation linked with the increased oxidative stress underlie degenerative changes in the aging neurons.
COBISS.SI-ID: 25347879
Conformational diseases constitute a group of heterologous disorders in which a constituent host protein undergoes changes in conformation, leading to aggregation and deposition. In order to understand the molecular mechanisms of amyloid-fibril formation, several in vitro and in vivo studies, thus including model and pathologically relevant proteins, have been performed. In this work we presented a detailed analysis of the mechanism by which proteins undergo ordered aggregation into amyloid fibrils classified in three groups, namely (a) templating and nucleation; (b) linear, colloid-like assembly of spherical oligomers; and (c) domain- swapping.
COBISS.SI-ID: 24680231
Based on the observation that progressive myoclonus epilepsies (PMEs) and neurodegenerative diseases share common features of neurodegeneration, in this work we proposed that both pathologies share common underlying molecular characteristics. It is well documented that autophagy is overloaded or impaired in neurodegenerative conditions, including Lafora disease (EPM2). Although additional research in this area will be necessary, we proposed that existing therapies for PMEs could be enhanced using similar drugs as those used for the treatment of neurodegenerative diseases.
COBISS.SI-ID: 24607527
In this work, we investigated the cell death termed apoptosis, in two tumor-cell lines, U937 and T98G, thus induced by the tumor necrosis factor (TNF)-alpha. The cell death involved lysosomal destabilization and the release of cathepsins into the cytosol. However, the blockage of cysteine cathepsins with a broad-spectrum inhibitor, E64d, or a more specific cathepsin B inhibitor, CA-074Me, had no effect on the progression of apoptosis in neither cell line, thus suggesting that TNF-alpha apoptosis is not critically dependent on cysteine cathepsins in these cellular models.
COBISS.SI-ID: 22717479
In this study, we showed that polyalanine tracts containing more than 23 repeats physically associate with mitochondria by a mechanism that induces cytochrome c release and caspase-3 activation, independently of the mitochondrial permeability transition pore (MPTP). These results suggest that oligomerized polyalanine tracts might induce the rupture of the mitochondrial membrane, the subsequent release of cytochrome c, and apoptosis. This novel mechanism for polyalanine tract cytotoxicity might be common to the pathoqenesis of all polyalanine diseases.
COBISS.SI-ID: 22793767