Ricerc@Sapienza

The conformational diseases are a group of pathologies characterised by the aggregation and tissue deposition of aberrant proteins. This is the molecular mechanism of a number of neurological conditions, including Alzheimer¿s and Huntington¿s diseases, the spongiform encephalopathies and the serpinopathies, human pathologies caused by mutations that promote polymerisation and intracellular deposition of proteins of the serpin superfamily, leading to a poorly understood cell toxicity and death. This mutations cause serpin polymerisation and retention within the endoplasmic reticulum of the cell of synthesis. Several such mutations have been found in neuroserpin. Human neuroserpin is a serpin mainly expressed by neurons and is responsible for a genetic disease known as Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). Its main symptoms are early onset dementia, epilepsy and neurodegeneration. So far, the exact mechanism of polymer toxicity is not completely clear. In this proposal, we aim to characterise the cell toxicity of neuroserpin polymers in our neural model of FENIB, focusing in particular on mitochondria and oxidative stress: in fact, we have found that cells expressing polymerogenic NS overexpress several anti-oxidant genes and undergo apoptosis when the anti-oxidant defences are blocked. Our preliminary results also suggest an alteration of mitochondrial physiology. Here we propose to further characterise the involvement of oxidative stress and mitochondria in the neuronal degeneration underlying the dementia FENIB.