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Cogo, Susanna (2018) Investigating the role of the Roc/GTPase domain of the Parkinson's disease kinase LRRK2 in regulating protein function and activity. [Ph.D. thesis]

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Abstract (italian or english)

Parkinson’s disease (PD) is the second most common neurodegenerative disease of the modern era. Although PD aetiology is still uncertain, approximately 10% of patients suffer from a monogenic form of PD. Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal dominant, late onset familial PD and increase PD risk. LRRK2 possesses dual Roc/GTPase and kinase domains, bridged by a COR scaffold. Given the robust association with PD and the presence of a “druggable” kinase activity, substantial efforts have been made to explore LRRK2 functions in health and disease. The current understanding of LRRK2 biology comes from the characterisation of knockout models or the manipulation of its kinase activity, especially since the most common pathological mutation is the G2019S in the kinase domain and kinase activity is associated with increased cellular toxicity. Conversely, Roc has received less attention, probably because of the challenges related to the measurement of in vitro GTPase activity. Nevertheless, the cross-talk between the two enzymatic modules and the signalling properties of Roc make the GTPase domain a key element in determining the biochemical and cellular properties of LRRK2. Therefore, a thorough characterisation of the intramolecular mechanisms of LRRK2 regulation as well as the signalling cascades orchestrated by the kinase is of high priority to provide alternative therapeutic targets in those cases where kinase inhibition proves badly-tolerated or ineffective. In this scenario, this project has focused on a comprehensive characterisation of the role of LRRK2-Roc in regulating protein biochemistry and the binding with the previously identified interactor p21-activated kinase 6 (PAK6). As a functional readout, two pathways convincingly linked to LRRK2, i.e. autophagy and neurite remodelling, have been investigated. Specifically, we characterised a murine cellular model where endogenous Lrrk2 has been genetically engineered to disrupt guanine nucleotides binding in terms of Lrrk2 expression levels, basal autophagy and the ability to respond to specific autophagic stimuli. We observed that lack of nucleotide binding in Roc affects protein steady-state levels and possibly the response to autophagy-inducing treatments. The second part of the study was dedicated to the characterisation of the interaction between LRRK2 and PAK6. PAK6 regulates actin-cytoskeletal dynamics and it was demonstrated by our group to interact with Roc and to promote neurite outgrowth in vivo through its kinase activity in a LRRK2- and GTP-dependent manner. More recently, we demonstrated that the two proteins bidirectionally modulate each other and overexpression of PAK6 is able to rescue the defects in neurite outgrowth associated with the G2019S pathological mutation. We then went a step further and, in collaboration with Dr. Patrick Lewis at University of Reading, we evaluated the impact of PAK6 pharmacological inhibition on autophagy, given the established role of LRRK2 and the importance of actin cytoskeleton in assisting the process, as well as the involvement of PAK6 homolog PAK1 in promoting autophagy through the AKT/mTOR/ULK1 axis. Our results show clear alterations in the autophagic markers analysed after treatment with an inhibitor of PAK6 kinase activity. Second, we characterised the effects of a de novo substitution in PAK6 in terms of kinase activity, localisation and neurite development as well as interaction with LRRK2, and the consequences of a PD mutation in Roc in terms of binding with PAK6. While the PAK6 variant does not affect the properties of the protein, the presence of a mutation in LRRK2-Roc impairs the interaction with PAK6, with possible consequences on downstream pathways. Overall, our data suggest that any alterations in Roc have severe implications for the steady-state levels of the protein, its activities and binding with partners, with a predicted impact on its subcellular localisation and downstream signalling.

Abstract (a different language)

La malattia di Parkinson (MP) è la seconda malattia neurodegenerativa più comune dell’era moderna. Nonostante un’eziologia incerta, il 10% dei pazienti soffre di una forma monogenica di MP. Mutazioni nel gene Leucine-rich repeat kinase 2 (LRRK2) sono la causa più comune di MP autosomica dominante ad insorgenza tardiva e aumentano il rischio di sviluppare la MP. LRRK2 possiede una duplice attività enzimatica: GTPasica nel dominio Roc e chinasica, collegate da un dominio COR. Date la robusta associazione con la MP e la presenza di un’attività chinasica modulabile dal punto di vista farmacologico, sono stati compiuti notevoli sforzi per esplorare il ruolo fisiopatologico di LRRK2. L’attuale comprensione della biologia di LRRK2 proviene dallo studio di modelli knockout o dalla manipolazione dell’attività chinasica, dato che la mutazione patologica più comune è la G2019S nel dominio chinasico e l’attività chinasica è associata ad aumentata tossicità cellulare. Al contrario, Roc ha ricevuto minore attenzione, probabilmente a seguito delle difficoltà nel misurare l’attività GTPasica in vitro. Tuttavia, l’interazione tra i due moduli enzimatici e le proprietà di signalling di Roc rendono il dominio GTPasico un elemento chiave nel determinare le proprietà biochimiche e cellulari di LRRK2. Una caratterizzazione completa dei meccanismi intramolecolari di regolazione e delle cascate di segnale orchestrate dal dominio chinasico è dunque un requisito essenziale per individuare strategie terapeutiche alternative qualora l’inibizione dell’attività chinasica fosse mal tollerata o inefficace. Questo progetto si è focalizzato su una caratterizzazione globale del ruolo di Roc nel regolare le proprietà biochimiche di LRRK2 ed il legame con un interattore precedentemente identificato, p21-activated kinase 6 (PAK6). A livello funzionale, sono stati investigati due processi associati a LRRK2 in modo convincente: autofagia e rimodellamento dei neuriti. Più precisamente, abbiamo caratterizzato un modello cellulare murino, in cui Lrrk2 endogena è stata ingegnerizzata geneticamente per impedire il legame dei nucleotidi guaninici, in termini di stabilità della proteina, autofagia basale e capacità di rispondere a stimoli autofagici. Abbiamo osservato che l’assenza di legame coi nucleotidi nel Roc influenza i livelli di Lrrk2 e la risposta all’induzione del flusso autofagico. La seconda parte dello studio riguarda la caratterizzazione dell’interazione LRRK2-PAK6. PAK6 regola le dinamiche del citoscheletro di actina. Il nostro gruppo ha dimostrato che PAK6 interagisce con Roc e promuove la crescita dei neuriti in vivo grazie alla sua attività chinasica in dipendenza da LRRK2 e dal GTP. Di recente, abbiamo dimostrato che le due proteine esercitano una vicendevole modulazione e la sovra-espressione di PAK6 può recuperare i difetti nella crescita dei neuriti associati alla mutazione G2019S in LRRK2. Abbiamo quindi fatto un passo ulteriore e, in collaborazione con il Dr. Patrick Lewis all’Università di Reading, abbiamo valutato l’impatto dell’inibizione farmacologica di PAK6 sull’autofagia, visto il ruolo assodato di LRRK2 e l’importanza del citoscheletro di actina nel processo, così come il coinvolgimento dell’omologo di PAK6, PAK1, nel promuovere l’autofagia tramite l’asse AKT/mTOR/ULK1. I nostri risultati mostrano chiare alterazioni nei markers autofagici analizzati a seguito del trattamento con un inibitore dell’attività chinasica di PAK6. Abbiamo poi caratterizzato gli effetti di una sostituzione de novo in PAK6 in termini di attività chinasica, localizzazione, sviluppo dei neuriti ed interazione con LRRK2, e le conseguenze di una mutazione patologica nel Roc in termini di legame con PAK6. Mentre la variante di PAK6 non influenza le proprietà della proteina, la mutazione nel Roc riduce l’interazione con PAK6. Globalmente, i nostri dati suggeriscono che qualunque alterazione di Roc abbia severe conseguenze per i livelli basali di LRRK2, l’attività della proteina ed il legame con gli interattori, con un probabile impatto sulla localizzazione subcellulare e le cascate di segnale a valle.

EPrint type:Ph.D. thesis
Tutor:Greggio, Elisa
Supervisor:Lewis, Patrick A.
Ph.D. course:Ciclo 31 > Corsi 31 > BIOSCIENZE
Data di deposito della tesi:30 November 2018
Anno di Pubblicazione:30 November 2018
Key Words:Parkinson's disease; Leucine-rich repeat kinase 2; Roc; autophagy; p21-activated kinase 2
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/09 Fisiologia
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:11475
Depositato il:07 Nov 2019 14:19
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