Universitą degli studi di Pavia


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Milani research activity

I’m currently developing my PhD research activity at the Laboratory of Experimental Neurobiolology directed by Dr. Cristina Cereda (National Neurological Institute C. Mondino, Pavia), in which we are studying the mechanisms involved in Amyotrophic Lateral Sclerosis (ALS), a multifactor and multigenic disorder with still unknown aetiology and pathogenesis. Even if several new genes associated to ALS have been described, SOD1 gene is considered the major gene involved in ALS pathogenesis.
The aim of my project is to investigate how the expression of this gene may be modulated under oxidative stress, a condition observed in ALS. In fact, studies to date on SOD1 gene have been mostly focused on alterations in the coding region and their associations with ALS. However, the importance to study SOD1 expression regulation at multiple levels is becoming clear, since altered SOD1 induction may be involved in ALS, as demonstrated by recent data showing increased SOD1 transcript levels in pathological tissues of sporadic ALS patients compared to control subjects (Gagliardi et al., 2010). We are focusing our attention on both the transcriptional induction and the post-transcriptional regulation, since it is well-documented that both the events could contribute to determine the global messenger RNA levels.

Furthermore, I’m working on another project with the aim to study SOD1 protein role(s) in the nuclear compartment. In fact, even if the first evidence of SOD1 localization in the nucleus dates back to more than twenty years ago, its function in this compartment remains poorly understood, probably because its well-defined enzymatic role in superoxide catalysis may have obscured or prevented investigation seeking unconventional/nondismutasic function(s) in the nuclear compartment. We hypothesize that SOD1 in the nucleus could be involved in gene expression regulation, acting as an “unconventional” DNA binding protein (uDBP) and/or a co-regulator for transcription. We also think that SOD1 mutations or post-translational modifications, such as oxidation, might modify its ability to interact with specific DNA sequences or nuclear proteins, altering transcription. Indeed, there are evidences of altered transcriptome in ALS (Kirbi et al., 2005). The availability of powerful genomics and proteomics technologies will allow us to test our hypothesis, thus unraveling complex regulatory and interactive pathways, potentially involved in ALS pathogenesis.

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