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Laboratory of Molecular Mechanisms of Polyglutamine Diseases

Head
Luana
Fioriti
Head of Laboratory
Neuroscience
luana.fioriti@marionegri.it
Senior Advisor
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The proteins involved in polyglutamine (PolyQ) diseases, such as Huntingtin (HTT) in Huntington's disease (HD), have peculiar characteristics compared to other pathological proteins. Huntingtin aggregates can be released from affected cells and be picked up by those that are still healthy. These observations have enormous implications for the therapy of Huntington's disease.

In the laboratory, we study the role of some structural aspects of polyQ aggregates in in the diffusion of such aggregates through the brain parenchyma, and the impact of such diffusion on the progression of the disease.

RESEARCH AREAS

Huntington disease: pathogenic contribution of Huntingtin aggregates

Protein aggregation observed in diseases such as Alzheimer's and Parkinson's is caused by their structural conversion from a native form into a pathological conformation rich in β-sheet type structures. HTT and other polyQ proteins aggregate with a different mechanism, through the formation of supercoiled helixes called coiled-coils (Ccs). CCs mediate protein-protein interactions, and are usually reversible. In the mutated HTT, following the expansion of the polyQ tract, the CC regions become more stable, promoting their aggregation and toxicity. We also observed that CCs are implicated in the intercellular propagation of HTT aggregates. In our studies we will identify the molecular mechanisms underlying these processes, with the goal to identify new therapeutic targets.

Huntington disease: intercellular propagation of Huntingtin aggregates (HTT)

The objective of our research is to study how the intercellular propagation of polyQ aggregates contributes to the progression of HD. It is believed that the late onset of the disease is caused by the age-dependent decline of the cells' ability to properly degrade aggregated proteins. However, another explanation could be that the spread of toxic aggregates in the brain is a limiting factor in the onset of the disease. Therefore, establishing a relationship between aggregation, spread and onset of disease symptoms will be of great importance, especially in the context of a possible therapeutic intervention.

Huntington disease: development of new therapeutic approaches

In this study we want to evaluate the therapeutic potential of an intervention aimed at affecting the CC structure of mutated HTT, to prevent or delay its aggregation. In particular we will examine if: it is possible to interfere with the oligomerization and toxicity of polyQ-CC-HTT in cell cultures and in vivo; and whether it is possible to block the intercellular transfer of the polyQ aggregates.

Front temporal Dementia: development of new cellular models to study the spreading of Tau oligomers

The aggregates of the microtubule-associated protein Tau are a pathological hallmark of tauopathies including front temporal dementia and Alzheimer’s disease. Tau oligomers are considered to be the most toxic species and the likely cause of the spreading of the disorders. Here, using a new cell culture system that we developed, we study the seeding properties and overall effects on cell metabolism of oligomers of the FTD-associated tauP301L mutant. We find that internalized oligomers promote the aggregation of endogenous tauP301L and appear resistant to degradation. The enhanced half-life of the aggregates correlates with a general decrease of proteasome activity and enhanced toxicity. These analyses provide new insights into the molecular determinants of the prion-like mechanism behind the spreading of tau pathology.

Phase separation of RNA Binding protein in physiology and pathology

Neurons have several membrane-less compartments generated by phase separation, including the postsynaptic density and elements of the presynapse, which are unique subcellular compartment that allow the neurons to function efficiently. Interestingly, many proteins associated with neurodegenerative disease are found in membrane-less organelles, particularly in stress and transport granules. These proteins are capable of phase separation and several hypotheses link membrane-less compartments to toxic aggregates observed in disease. Of particular interest is the hypothesis that the protein and RNA inclusions formed in disease are related to the functional complexes occurring inside these membrane-less organelles. Post-translational modifications (PTMs), which can alter phase separation, can modulate membrane-less formation and provide potential new therapeutic strategies for currently untreatable neurodegenerative diseases. For example Tau can interact with RNA binding proteins, in particular TIA-1, and co-localizes with them in complex called Stress Granules. When Tau is colocalized in Stress Granules with TIA-1, Tau is more insoluble and becomes toxic to neurons. One hypothesis for the role of SG in neurodegenerative disease consider them as seeding starting point that trigger Tau aggregation and propagation. We recently discovered that Tau interacts with the translational regulator CPEB3, which also resides in phase separated organelles called P-bodies. We are currently exploring the pathophysiological relevance of this newly identified interaction in the context of Alzheimer's disease and Frontotemporal dementia.

Head Unit
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Staff
Franca
Orsini
Researcher
franca.orsini@marionegri.it
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Codice:

International Consensus on Cardiopulmonary Resuscitation.

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Head
Luana
Fioriti
Head of Laboratory
Neuroscience
luana.fioriti@marionegri.it
Senior Advisor
No items found.

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