Heat shock proteins agiscono sull'interazione tra omeostasi proteica e lipidica: Implicazioni per la malattia di Parkinson
Year: 2023
Type: dissertation
Abstract: Loss of protein homeostasis is associated with the accumulation of misfolded, condensed and aggregated forms of proteins, as well as with a wide range of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases.Cells evolved a sophisticated protein quality control system to maintain protein homeostasis that includes molecular chaperones and degradation systems.Heat shock proteins (HSPs) are a class of molecular chaperones: they survey protein folding, prevent protein aggregation, and target damaged proteins to degradation.Several stimuli, beyond heat shock, can upregulate HSPs expression, which participate not only in the cell stress response, but exert also housekeeping functions, and may even regulate development and differentiation.Tremendous advances have been made in the last decades in understanding how HSPs are transcriptionally regulated.However, how stress signals are perceived by the cells and are integrated to activate the heat shock response is still only partly understood.Changes in the physical state and lipid composition of cell membranes can activate the expression of HSPs, through yet unclear mechanisms.HSPs, in turn, can directly interact with lipids, thereby modulating the physical state of lipid membranes.Intriguingly, changes of the lipidome can elicit protein condensation and aggregation, and dysfunction in lipid homeostasis is a known risk factor of many neurodegenerative diseases.Taken together, these data highlight the existence of a cross-talk between lipid and protein homeostasis.Based on their ability to interact both with proteins and lipids, one may envisage that HSPs represent key players acting at the crossroad between lipid and protein homeostasis.In this PhD thesis, we tackled this hypothesis using in vitro systems and cellular models.We used as a model system α-synuclein, a protein whose aggregation can be triggered by interaction with small lipid unilamellar vesicles (SUVs).We investigated whether recombinant small HSPs displace αsynuclein from lipids, reducing its aggregation (in collaboration with Prof. Vendruscolo, Cambridge University, UK).Our data demonstrate that, besides acting at the protein level and blocking αsynuclein aggregation by direct protein-protein interactions, small HSPs can interact with lipids, interfering with both lipid and protein dynamics and aggregation.Next, we investigated whether changes in the physical state of the lipid membranes can induce the expression of HSPs.To do so, we used the aminosterol trodusquemine as a model system.Trodusquemine interacts with lipid membranes and changes their fluidity.It also prevents αsynuclein lipid-induced aggregation.Using cellular systems, we could show that trodusquemine acts as a co-inducer of the heat shock response, potentiating the expression of key HSPs.These, in turn, can synergize with trodusquemine to block protein misfolding and aggregation and help restoring lipid homeostasis.In conclusion, this PhD work contributes to deciphering how cells regulate the cross-talk between lipid and protein homeostasis, and provides an example of how these processes may be pharmacologically exploited to combat protein aggregation.
Language: Italian
Topic: Heat shock proteins research
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7019614361