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Tosatto, Laura (2009) Insights on alpha-synuclein interaction network and aggregation pattern. [Ph.D. thesis]

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Abstract (english)

Parkinson’s disease (PD) is the most important neurodegenerative disease which regards movement. The 1% of the population over 65 years old is affected by this disorder. The main symptoms are bradykinesia, resting tremor, postural instability, muscle rigidity and sometimes cognitive and personality problems. The cause of the disease is a selective death of dopaminergic neurons in substantia nigra pars compacta. Actually, the best therapy can help to solve only symptoms and it is based on the supply of the precursor of dopamine, which is the neurotransmitter lacking in the disease, or inhibitors of the activity of enzymes involved in the metabolism of dopamine. This therapy does not prevent further neuronal loss. Two are the links that correlate the protein alpha-synuclein (?-syn) to PD: this protein is found as amyloid fibrils in proteinaceous aggregates known as Lewy bodies, which are present in PD patients’ brains, and second, single point mutation of ?-syn are correlated to early onset of autosomic dominant forms of the disease. In this frame an understanding the molecular cause that lead to neuronal loss and protein aggregation becomes crucial for the development of new therapeutic strategies.
?-Syn is expressed in all the central nervous system and it is localized at the presynaptic terminal but its biological role is still not clear. ?-Syn is natively unfolded and it is able to acquire different conformations in different conditions such as the presence of membranes or organic solvents. The central region of the protein is able to fold into ?-sheet structure comparable with amyloid fibrils found in Lewy bodies. Point mutants implied in the early onset PD (A30P, E46K and A53T) have a higher propensity for the formation of oligomers. Recently, the hypothesis that the oligomers are the main cause of ?-syn toxicity is gaining support. Studying the oligomerization process seem to be now more important for the comprehension of neuronal death. The first steps of self-interaction are extremely rare events and thus difficult to observe with bulk methods; fibrils are insoluble, so structure can not be solved by NMR, nor by X-ray crystallography.
Moreover, ?-syn was found to interact with a wide variety of proteins as detected by co-immunoprecipitation or affinity techniques. The biological relevance and the molecular basis of this processes require further investigation by high resolution methods like NMR (Nuclear Magnetic Resonance) or SPR (Surface Plasmon Resonance). Furthermore, every interacting partners may sequester ?-syn from cytosol to decrease the probability of self-interaction that lead to aggregation.
In this PhD thesis investigations were done in order to improve ?-syn interaction network knowledge. As any event correlated with an altered balance of ?-syn interaction network may favour ?-syn self-interaction, the experimental approach was divided into three parts to get information about: protein-protein interaction, membrane binding and aggregation studies.
SPR studies was performed to verify the interaction between ?-syn and 14-3-3?. 14-3-3 chaperone family can bind and regulate a wide variety of proteins. Sato et al. (2006) measured 1.1 ?M dissociation constant between ?-syn and 14-3-3? by SPR. However, these data were not reproduced, and also HSQC spectra of 15N labelled ?-syn in the presence of a three molar excess of 14-3-3? did not provide evidences of an interaction between the two molecules.
Interaction between membranes and ?-syn was studied by circular dichroism (CD). The first hundred residues of the proteins acquire ?-helix structure upon binding with micelles and liposomes. Interesting data come from the interaction between ?-syn dimers formed by two mutants produced in our lab (V3C and Syn141C): the dimer formed by disulfide bond between the Cys at the C-terminal end of the protein (C-term dimer) forms a distorted ?-helix upon the binding with 50 nm diameter small unilamellar vesicles (SUVs) composed of 50% DMPG 50% DMPC, while the dimer formed by V3C mutants (N-term dimer) acquires an amount of ?-helix comparable to the one observed upon binding to SDS micelles. It is possible that SUV dimensions (i.e. curvature) and the covalent constrain in C-term dimer are the cause of helix distortion.
Finally, self-interaction of ?-syn was investigated by fibrillogenesis and aggregation assays. Fibrillogenesis was monitored with Thioflavin T (ThT) fluorescence; samples of wild-type ?-syn, C-term dimer, pathological mutant A30P, E46K and A53T were incubated at 37°C under shaking; aliquots were collected at fixed time, mixed with ThT solution and fluorescence intensity measured at 485 nm. This assay revealed that E46K, A53T and C-term dimer form fibrils faster than wild-type ?-syn and the A30P mutant presents a longer lag phase. It was not possible to obtain good sigmoidal curves with this method in the case of ?-syn, probably because of ?-syn fibrils disruption or precipitation and light scattering events. Hence, a protocol applied by Lük et al. (2007) was applied. This method measures fluorescence polarization (FP) of samples of ?-syn incubated in a 96 wells plate at 37°C under agitation. ?-Syn wild type protein, pathological mutants, C-term and N-term dimer were mixed with Oregon Green 488 maleimide labelled ?-syn (1:100=Syn-OregonGreen:?-syn), to then measured FP variations in time. The comparison between the samples shows that wild-type ?-syn aggregates faster than pathological mutants and N-term dimer. The C-term dimer shows an increase of FP with the shortest lag phase. The covalent constrain seem to favour intramolecular interaction and then aggregation and fibrillogenesis. NMR spectra was recorded for C-term dimer formed with 1:5 protein mixture of 15N labelled Cys C-term mutant : 14N Cys C-term mutant, but no intramolecular interaction was detected. In addition, ?-syn was tested in the presence of three proteins. While DJ1 provides no significance effect on ?-syn aggregation, 3T protein seem to have an aspecific influence on oligomers enlargement rate. Moreover, 14-3-3? mixed in three molar ratios to ?-syn seems to have a concentration dependent effect on ?-syn aggregation, although experimental errors do not allow a conclusive interpretation of this finding. However, 1:1=14-3-3?:?-syn shows significantly slower aggregation rate compared to ?-syn incubated alone.
In conclusion, progress on the understanding on the molecular mechanism of ?-syn aggregation was reached, specifically for what concern the orientation of intramolecular interaction that lead to the formation of oligomers and fibrils, and proteins able to host ?-syn oligomers growth. Moreover, a new method based on fluorescence polarization was used to reveal differences on lag phase and rate of the aggregation process of ?-syn and its variants. This technique can be use to test conditions, molecules and proteins able affect the aggregation of ?-syn.

Abstract (italian)

Il morbo di Parkinson (PD) è la più importante malattia neurodegenerativa riguardante la funzionalità motoria. L'1% della popolazione sopra i 65 anni è affetto da questa malattia. I sintomi principali sono bradichinesia, tremore a riposo, instabilità posturale, rigidità muscolare e, talvolta, problemi cognitivi e della personalità. La causa della malattia è una morte selettiva dei neuroni dopaminergici nella substantia nigra pars compacta. In realtà, la migliore terapia attualmente applicata è puramente sintomatica, e si basa sulla somministrazione del precursore della dopamina, che è il neurotrasmettitore assente nella malattia, o su inibitori delle attività degli enzimi coinvolti nel metabolismo della dopamina. Questa terapia non impedisce un’ulteriore perdita neuronale. Due evidenze correlano la proteina alfa-sinucleina (?-syn) al PD: questa proteina è presente come fibrille amiloidi in aggregati proteici noti come corpi di Lewy, che sono presenti nel cervello dei pazienti, e in secondo luogo, mutazioni di un singolo amminoacido del gene di ?-syn sono correlati all’insorgenza di forme precoci della malattia, con trasmissione autosomica dominante. In questo contesto, la comprensione delle cause molecolari che conducono alla perdita di neuroni e all’aggregazione di ?-syn diventa fondamentale per lo sviluppo di nuove strategie terapeutiche.
?-Syn è espressa in tutto il sistema nervoso centrale ed è localizzata presso i terminali presinaptici, tuttavia il suo ruolo biologico non è ancora chiaro. ?-Syn è una natively unfolded protein, ma è in grado di acquisire conformazioni diverse in diverse condizioni, quali la presenza di membrane o solventi organici. La regione centrale della proteina è in grado di acquisire strutture a foglietto ? nelle fibrille amiloidi che vengono riscontrate nei corpi di Lewy. I mutanti patologici (A30P, E46K e A53T) hanno una maggiore propensione per la formazione di oligomeri. Recentemente, si sta rafforzando l'ipotesi che gli oligomeri siano la principale causa della tossicità causata da ?-syn. Studiare il processo di oligomerizzazione è quindi di enorme importanza per la comprensione dei processi che portano alla morte neuronale. I primi passaggi nella creazione di piccoli aggregati sono eventi estremamente rari, e quindi difficili da osservare con maggior parte dei metodi; in più, essendo le fibrille insolubili, la loro struttura non può essere risolta da NMR, né dalla cristallografia a Raggi-X.
Diversi studi riportano l’interazione di ?-syn con una grande varietà di proteine, come rilevato da esperimenti di co-immunoprecipitazione o cromatografia di affinità. La rilevanza biologica e la base molecolare di questo processo necessitano di un'ulteriore indagine con metodi ad alta risoluzione come NMR (Risonanza Magnetica Nucleare) o SPR (Surface Plasmon Resonance). Inoltre, tutte le macromolecole in grado di interagire con ?-syn ne provocano il sequestro dal citosol, diminuendo le probabilità di auto-interazione che portano alla sua aggregazione.
In questa tesi di dottorato sono stati realizzati studi al fine di ampliare la conoscenza sulla rete di interazione di ?-syn. Dal momento che ogni evento correlato ad un alterato l'equilibrio nel network di interazioni di ?-syn può favorire la fibrillogenesi, l'approccio sperimentale è stato diviso in tre parti: interazioni proteina-proteina, legame alle membrane e studi di aggregazione.
Esperimenti mediante SPR sono stati effettuati per verificare l'interazione tra ?-syn e 14-3-3?. La famiglia di chaperone 14-3-3 può interagire e regolare una grande varietà di proteine. Sato et al. (2006) hanno misurato con tecniche SPR la costante di dissociazione tra ? e syn-14-3-3?, riportando un valore di (1,1 ?M). Negli esperimenti effettuati questo dato non è stato riprodotto, e anche lo spettro HSQC di ?-syn marcata con 15N in presenza di tre volte eccesso molare di 14-3-3? non ha fornito prove di un’interazione tra le due molecole.
Il legame alle membrane di ?-syn è stato studiato mediante dicroismo circolare (CD). I primi 100 residui della proteina sono in grado di acquisire struttura ?-elicoidale in presenza di micelle e liposomi carichi negativamente. Dati interessanti provengono dallo studio di dimeri di ?-syn costituiti da due mutanti prodotti nel nostro laboratorio (V3C e Syn141C): l’omodimero formato da un ponte disolfuro tra la cisteina posizionata al C-terminale della proteina (dimero C-term) forma un’?-elica distorta in presenza di liposomi di 50 nm di diametro, composti di 50% DMPG 50% DMPC. Il dimero formato dal mutante V3C (dimero N-term) acquisisce struttura ?-elicoidale paragonabile a quella osservata per il legame con micelle di SDS. È possibile che la dimensione (cioè la curvatura) dei liposomi e il legame covalente vincolante la coda C-terminale nel dimero C-term siano la causa dell’alterazione della struttura dell’?-elica.
Infine, la self-interazione di ?-syn è stata oggetto di indagine con saggi di fibrillogenesi e di aggregazione. La formazione di fibrille è stata rilevata sulla base della variazione di intensità della fluorescenza della molecola Tioflavina T (ThT); campioni di wild-type ?-syn, dimero C-term e mutanti patologici A30P, E46K e A53T sono stati incubati a 37 °C sotto agitazione; aliquote sono state raccolte a tempi fissi, miscelate con una soluzione di ThT e l’intensità di fluorescenza misurata a 485 nm. Il test ha rivelato che E46K, A53T e il dimero C-term formano fibrille più velocemente rispetto a wild-type ?-syn, il mutante A30P presenta invece un ritardo nella lag-phase. Non è stato possibile ottenere una buona interpolazione dei dati con questo metodo, probabilmente a causa della precipitazione o della rottura delle fibrille di ?-syn, o di eventi di light scattering in cuvetta dovuti alle fibrille. Pertanto, un protocollo pubblicato da Luk et al. (2007) è stato applicato. Questo metodo misura l’aumento della polarizzazione di fluorescenza (FP) di campioni di ?-syn incubati a 37 °C sotto agitazione in una piastra a 96 pozzetti. ?-Syn wild-type, mutanti patologici, dimeri C-term ed N-term sono stati mescolati con ?-syn marcata con Oregon Green 488 (1:100 = Syn-OregonGreen: syn-?), e le variazioni nel tempo di FP sono state registrate. Il confronto tra i campioni dimostra che ?-syn wild-type aggrega più veloce rispetto ai mutanti patologici e al dimero N-term, mentre il dimero C-term presenta il più veloce aumento di FP, con la minor lag-phase.. Il legame covalente al C-terminale sembra favorire l'interazione intramolecolare e quindi l'aggregazione e la fibrillogenesi. Lo spettro NMR è stato registrato per il dimero C-term formato per il 20% da molecole di ?-syn marcate con 15N, ma non è stata rilevata interazione intramolecolare. Inoltre, l’aggregazione di ?-syn è stata testata in presenza di tre proteine. Mentre la presenza di DJ1 non comporta effetti statisticamente significatici sull’aggregazione di ?-syn, la proteina chimerica 3T influenza la velocità di ingrandimento degli oligomeri di ?-syn. Inoltre, il chaperone 14-3-3? mescolato in tre rapporti molari con ?-syn sembra avere un effetto concentrazione dipendente sull’aggregazione di ?-syn, anche se gli errori sperimentali non consentono una interpretazione conclusiva di questa osservazione. Tuttavia, ?-syn in presenza di 14-3-3? equimolare mostra una velocità di aggregazione significativamente più lenta rispetto ai campioni di ?-syn incubati in assenza di 14-3-3?.
In conclusione, sono stati raggiunti dei progressi sulla comprensione sul meccanismo molecolare di aggregazione ?-syn, in particolare per ciò che riguarda l'orientamento dell’interazione intramolecolare che porta alla formazione di oligomeri e fibrille, e le proteine in grado di ostacolare la crescita di oligomeri di ?-syn. Inoltre, un nuovo metodo basato sulla polarizzazione di fluorescenza è stata utilizzato per rilevare differenze in velocità di aggregazione e lag phase tra ?-syn e sue varianti. Questa tecnica può essere utilizzata per testare diverse condizioni, molecole e proteine in grado di influenzare l'aggregazione in vitro di ?-syn.

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EPrint type:Ph.D. thesis
Tutor:Bubacco, Luigi
Ph.D. course:Ciclo 21 > Scuole per il 21simo ciclo > BIOCHIMICA E BIOTECNOLOGIE > BIOTECNOLOGIE
Data di deposito della tesi:01 February 2009
Anno di Pubblicazione:02 February 2009
Key Words:alpha-synuclein, Parkinson's disease, protein-protein interaction, aggregation, fibrillogenesis, fluorescence polarization
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/09 Fisiologia
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:1903
Depositato il:01 Feb 2009
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