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Rossi, Alice (2018) Effects of Presenilin 2 mutations associated with Familial Alzheimer's Disease on mitochondrial bioenergetics. [Ph.D. thesis]

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Abstract (english)

Alzheimer’s Disease (AD) is a neurodegenerative disorder of the central nervous system. It is mainly sporadic, however, a little percentage of cases is inherited (Familial AD, FAD) and due to autosomal dominant mutations on three different genes, coding for Amyloid Precursor Protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2). Presenilins, mainly localized at Endoplasmic Reticulum (ER) membranes, are the catalytic core of the ɣ-secretase complex, although several ɣ-secretase-independent activities of PSs, such as modulation of neurites outgrowth, apoptosis, autophagy, synaptic functions and regulation of Ca2+ homeostasis, have been described.
Ca2+, a key intracellular second messenger, is involved in multiple cellular functionalities. Interestingly, alterations in Ca2+ homeostasis have been proposed as an early event in different neurodegenerative diseases, including AD. Notably, FAD-PS mutants have been reported to be directly involved in these dysregulations. In our lab, it has been previously showed that PS2 expression, both WT and, more potently, FAD mutants (such as PS2-T122R), but not PS1, decreases the ER Ca2+ content, mainly by inhibiting SERCA pump activity. Moreover, PS2 increases ER-mitochondria physical and functional coupling, favouring the process of ER to mitochondria Ca2+ transfer. However, due to its effect on ER [Ca2+], which results in a lower amount of available Ca2+ within the ER, its expression dampens mitochondrial Ca2+ rises upon cell stimulation.
Based on the well-established role of Ca2+ on mitochondrial metabolism, here we investigate the possible effects on mitochondrial functionalities of the complex balance between alterations in ER Ca2+ content and increased ER-mitochondria coupling, induced by FAD-PS2 mutants expression. A neuroblastoma cell line (SH-SY5Y) grown in a medium containing galactose, as a substitute of glucose, has been used. This growth condition enhances mitochondrial metabolism and results in an excellent experimental protocol to visualize possible mitochondrial defects.
Lower total cellular ATP levels were measured in FAD-PS2-T122R expressing cells, grown either in glucose- or galactose-containing medium, with the reduction more evident in the latter condition, thus suggesting possible mitochondrial defects induced by PS2 expression.
In order to investigate how Ca2+ dysregulation induced by PS2 could influence mitochondrial metabolism, we stimulated mitochondrial ATP production inducing ER Ca2+ release, followed by mitochondria Ca2+ uptake, using both bradykinin, as a maximal IP3R stimulation, and Fetal Calf Serum (FCS), as a more physiological stimulus. In both conditions, a reduction in mitochondrial ATP production, measured by a mitochondrial luciferase-based ATP probe, has been observed in cells expressing FAD-PS2, but not PS1. The defects in ATP synthesis were observed in SH-SY5Y, MEF, HT22 cells and in cortical neurons from PS2-N141I transgenic (Tg) mice (PS2.30H), by employing FRET-based ATP probes (ATeam 1.03) specifically targeted to the mitochondrial matrix or the nucleus. We also evaluated the glycolytic flux in these cells, by both employing a cytosolic luciferase-based ATP probe and measuring the extracellular medium acidification, but we did not observed any difference in these two parameters in FAD-PS2 expressing cells, compared to controls.
In order to understand the mechanism through which PS2 causes the observed mitochondrial dysfunction, we firstly considered the marked Ca2+ dysregulation induced by PS2 expression. We thus decided to modulate Ca 2+ handling in control cells, to mimic the ER Ca2+ depletion caused by PS2 expression. We used two different approaches: i) treating control cells with a SERCA pump inhibitor (Cyclopiazonic acid, CPA), to partially reduce the ER Ca2+ content, or ii) overexpressing a mutated-MICU1 (MICU1mut), a component of the mitochondrial Ca2+ uniporter complex. Although both approaches were able to reduce the capacity of control cells to produce ATP, for similar mitochondrial Ca2+ uptake in control and PS2-expressing cells, a lower mitochondrial ATP production in FAD-PS2 expressing-cells compared to CPA-treated or MICU1mut expressing controls was still observed. Taken together, these results suggest that part of the FAD-PS2-induced defects in mitochondrial metabolism is due to a reduced ER Ca2+ content and, consequently, mitochondrial Ca2+ uptake, negatively regulating the Ca2+-dependent mitochondrial metabolism. However, additional mechanisms, induced by FAD-PS2, are likely involved in mitochondrial dysfunctions. We thus evaluated the respiratory chain activity measuring the oxygen consumption rate (OCR): both basal and maximal OCR were reduced in FAD-PS2, but not in FAD-PS1, expressing cells. Moreover, a reduced mitochondrial ATP-linked respiration was measured in PS2-T122R expressing cells, while no difference was found in the proton leak.
Since the expression levels of the ATP synthase and the respiratory chain complexes were not affected by FAD-PS2 expression, and isolated mitochondria from WT and PS2-N141I Tg mice did not reveal substantial differences in mitochondrial respiratory activity, we reasoned that the impairment in ATP production observed in intact cells is not due to defective mitochondria per se, but likely depends on the cellular environment.
Importantly, for a proper mitochondrial metabolism, the right amount of substrates produced through glycolysis in the cytosol has to reach the mitochondrial matrix to support the TCA cycle and the respiratory chain activity. Hexokinase1 (HK1), the enzyme that catalyses the first step of glycolysis converting glucose to glucose 6-phosphate, seems to be involved in the modulation of the mitochondrial substrates import, since HK1 interaction/detachment with/from mitochondria can modulate mitochondrial substrates permeability. Firstly, we measured a reduced HK1-mitochondria co-localization in FAD-PS2 expressing SH-SY5Y cells, in FAD-PS2 patient-derived fibroblasts and in primary cortical neurons from FAD-PS2-N141I Tg mice, compared to controls. By mimicking the FAD-PS2 effect on HK1-mitochondria interaction treating control cells with Clotrimazole, a drug capable to detach HK1 from mitochondria, a reduced mitochondrial ATP production was measured; however, the impairment on ATP production induced by clotrimazole was less marked than that caused by FAD-PS2 expression. These results indicate that, although the detachment of HK1 from mitochondria plays a pivotal role in causing mitochondrial defects upon FAD-PS2 expression, the PS2-induced Ca2+ dysregulation, described above, may additionally contribute to the overall mitochondrial impairment. These results have been confirmed also by a genetic approach. We down-regulated the expression of endogenous HK1, by specific siRNAs, and we rescued HK1 protein level by over-expressing siRNA-resistant full-length- (FL-HK1) or truncated- (Tr-HK1) HK1. This latter protein lacks the mitochondrial binding domain, but still conserves the catalytic activity. We found that, upon endogenous HK1 silencing, mitochondrial ATP production is strongly reduced. Interestingly, while the re-expression of FL-HK1 was able to completely rescue the reduced ATP production, the Tr-HK1 was unable to do it, again confirming that the detachment of HK1 from mitochondria is involved in the mitochondrial impairment caused by FAD-PS2.
Related to HK1 and its role in the regulation of mitochondrial substrates permeability, an increase in the cytosolic amount of pyruvate was measured in FAD-PS2 expressing cells, compared to controls, employing a cytosolic FRET-based pyruvate probe, Pyronic. Importantly, by pharmacologically blocking mitochondrial pyruvate carrier (MPC), the protein responsible for mitochondrial pyruvate uptake, with two different drugs, UK5099 and Pioglitazone, no differences were anymore detected between control and FAD-PS2 expressing cells, suggesting that FAD-PS2 is acting on this pathway.
Overall, we have showed that FAD-PS2 mutants decrease cellular ATP levels, in particular mitochondrial ATP production, by two different mechanisms: 1) causing Ca2+ dysregulation, mainly decreasing the ER Ca2+ content, and thus the amount of Ca2+ available for mitochondrial Ca2+ uptake; 2) inducing the detachment of HK1 from mitochondria, likely affecting the availability of substrates (i.e., pyruvate) for mitochondria. Further experiments will be aimed at: i) evaluate the impact of the PS2-dependent strengthened ER-mitochondria coupling on the reported mitochondrial defects; ii) defining the molecular mechanism through which FAD- PS2 mutants affect HK1 intracellular distribution; iii) evaluate the impact of these alterations on the onset/progression of the AD phenotype.

Abstract (italian)

La malattia di Alzheimer è un disturbo neurodegenerativo del sistema nervoso centrale. È, principalmente, una malattia sporadica; tuttavia in una piccola percentuale di casi è ereditata e dovuta a mutazioni autosomiche dominanti in tre diversi geni, che codificano per la Proteina Precursore dell’Amiloide (APP), per Presenilina1 (PS1) e per Presenilina2 (PS2). Le preseniline, principalmente localizzate nella membrana del reticolo endoplasmatico (RE), costituiscono la porzione catalitica del complesso enzimatico della ɣ-secretasi. Le stesse, oltre ad essere fondamentali per l’attività di questo complesso enzimatico, hanno molte funzioni che sono indipendenti dalla ɣ-secretasi; tra queste, la modulazione della crescita dei neuriti, dell’apoptosi, dell’autofagia, delle funzioni sinaptiche e dell’omeostasi del Ca2+.
Il Ca2+ è un secondo messaggero intracellulare fondamentale, coinvolto in molteplici funzionalità cellulari; alterazioni dell'omeostasi del Ca2+ sono state proposte come eventi precoci in diverse malattie neurodegenerative, tra cui la malattia di Alzheimer. In particolare, è stato dimostrato che mutazioni in PS2 associate a forme familiari di Alzheimer (FAD) sono direttamente coinvolte in queste alterazioni. Nel nostro laboratorio è stato precedentemente dimostrato che l'espressione di PS2, sia della forma WT ma soprattutto delle forme mutate associate a FAD (come PS2-T122R), ma non di PS1, riduce il contenuto di Ca2 + nel RE principalmente inibendo l'attività della pompa SERCA. PS2, inoltre, aumenta la vicinanza fisica e funzionale di RE e mitocondri, favorendo il processo di trasferimento di Ca2+ tra i due organelli; tuttavia, a causa del suo effetto sulla [Ca2+] nel RE, che ha come conseguenza una minore quantità di Ca2 + disponibile per il rilascio nel citosol, la quantità di Ca2 + che entra nei mitocondri, dopo stimolazione, è ridotta.
Sulla base del ruolo fondamentale svolto dal Ca2 + nella regolazione del metabolismo mitocondriale, nel lavoro presentato in questa tesi abbiamo esaminato i possibili effetti sulla funzionalità mitocondriale del complesso equilibrio tra alterazioni del contenuto di Ca2+ nel RE e l’aumento della vicinanza tra RE e mitocondri, indotti dall’espressione di forme mutate di PS2 legate a FAD. Per svolgere questo studio abbiamo utilizzato una linea cellulare di neuroblastoma (SH-SY5Y), cresciuta in un terreno contenente galattosio, invece di glucosio. Infatti, le cellule cresciute in un terreno che contiene galattosio aumentano il metabolismo mitocondriale, rendendo così questo protocollo sperimentale ottimale per evidenziare eventuali difetti mitocondriali.
In cellule esprimenti FAD-PS2-T122R, cresciute in un terreno contenente glucosio o galattosio, sono stati misurati livelli totali di ATP cellulare minori rispetto a quelli di cellule di controllo. La riduzione di questo parametro era più evidente in cellule cresciute in terreno contenente galattosio, suggerendo possibili difetti mitocondriali indotti da PS2.
Per studiare come la deregolazione del Ca2+, causata dall'espressione di PS2, possa influenzare il metabolismo mitocondriale, abbiamo indotto il rilascio di Ca2+ dal RE, a cui segue un aumento di Ca2+ nei mitocondri che conseguentemente stimola la produzione di ATP mitocondriale. A tal fine abbiamo utilizzato sia bradichinina, come stimolo massimale del recettore IP3, sia siero fetale di vitello (FCS), contenente fattori che inducono una stimolazione più fisiologica dello stesso recettore. In entrambe le condizioni, è stata osservata una riduzione nella produzione di ATP mitocondriale, misurata utilizzando luciferasi (in particolare la sonda mitocondriale), in cellule esprimenti FAD-PS2, ma non in cellule che esprimevano FAD-PS1. I difetti nella sintesi di ATP sono stati osservati in cellule SH-SY5Y, MEF, HT22 e in neuroni corticali di topi FAD-PS2-N141I (Tg, PS2.30H), utilizzando anche sonde per l’ATP basate su FRET (ATeam 1.03), contemporaneamente espresse nella matrice mitocondriale e nel nucleo. Abbiamo anche valutato se l’espressione di FAD-PS2 potesse influenzare la glicolisi; per fare questo, abbiamo espresso in cellule una luciferasi citosolica, per valutare l’ATP prodotta nel citoplasma, e abbiamo misurato l’acidificazione del mezzo extracellulare, come indice di glicolisi. Per entrambe i parametri, non abbiamo osservato alcuna differenza tra cellule esprimenti FAD-PS2 o di controllo.
Per comprendere il meccanismo attraverso il quale PS2 causa la disfunzione mitocondriale osservata, data la nota deregolazione dell’omeostasi del Ca2+ indotta da PS2, abbiamo innanzitutto deciso di simulare la deplezione di Ca2+ nel RE causata dall’espressione di PS2 nelle cellule di controllo. Abbiamo usato due approcci diversi: da un lato abbiamo trattato le cellule di controllo con un inibitore della pompa SERCA (acido ciclopiazonico, CPA) per ridurre il contenuto di Ca2+ nel RE, dall’altro abbiamo sovraespresso una forma mutata di MICU1 (MICU1mut). In entrambi i casi abbiamo ottenuto una riduzione nell’entrata di Ca2+ nel mitocondrio, mimando perfettamente il difetto causato dall’espressione di FAD-PS2. Come atteso, il trattamento con CPA e l'overepressione di MICU1mut riducono notevolmente la produzione di ATP rispetto alle cellule di controllo non trattate. Ciononostante, a parità di Ca2+ che entra nel mitocondrio in cellule esprimenti o meno FAD-PS2, abbiamo misurato una minore produzione di ATP mitocondriale in cellule esprimenti forme mutate di PS2, rispetto ai controlli trattati con CPA o esprimenti MICU1mut. Tali risultati suggeriscono che i difetti nel metabolismo mitocondriale indotti dall’espressione di FAD-PS2 solo almeno in parte riconducibili alla riduzione del contenuto di Ca2+ nel RE, e quindi al suo ingresso nei mitocondri. Tuttavia, sono probabilmente coinvolti meccanismi aggiuntivi nelle disfunzioni mitocondriali osservate. Abbiamo, quindi, valutato l'attività della catena respiratoria misurando la velocità nel consumo di ossigeno (OCR). E’ stato così possibile osservare che sia il consumo di ossigeno a basale che il massimo consumo di ossigeno sono ridotti in cellule esprimenti FAD-PS2, ma non FAD-PS1. Inoltre, in cellule esprimenti PS2-T122R è stata misurata una riduzione della respirazione mitocondriale legata alla produzione di ATP. Tuttavia, poiché i livelli di espressione dell’ATP sintasi e dei complessi della catena respiratoria non variano, in seguito all’espressione di PS2, e dato che misure di respirazione in mitocondri isolati da topi WT e PS2-N141I Tg non hanno rivelato differenze sostanziali, la riduzione nella produzione di ATP osservata in cellule intatta non è verosimilmente dovuta ad un’alterazione intrinseca nell'attività della catena respiratoria. Questo suggerisce che i difetti riscontrati possano dipendere dall'ambiente cellulare, piuttosto che da un difetto intrinseco degli stessi mitocondri.
Per un corretto metabolismo mitocondriale, la giusta quantità di substrati prodotti nel citoplasma attraverso la glicolisi deve raggiungere la matrice mitocondriale per supportare il ciclo di Krebs e l'attività della catena respiratoria. L’esochinasi 1 (HK1), enzima che catalizza la prima reazione della glicolisi, convertendo il glucosio in glucosio 6-fosfato, sembra anche modulare l’ingresso dei substrati nei mitocondri, poiché l'interazione/distacco di HK1 con/dai mitocondri può modulare la permeabilità mitocondriale ai substrati. Abbiamo misurato una riduzione nella co-localizzazione tra HK1 e mitocondri in cellule SH-SY5Y esprimenti FAD-PS2, in fibroblasti da pazienti FAD con mutazioni in -PS2 e in neuroni corticali da topi transgenici FAD-PS2. Il trattamento di cellule di controllo con clotrimazolo, una sostanza nota per avere la capacità di indurre il distacco di HK1 dai mitocondri, si è rivelato capace di ridurre la colocalizzazione tra HK1 e mitocondri a un livello simile a quello causato da PS2, mimandone così l'effetto. In seguito a questo trattamento, cellule di controllo mostravano una ridotta produzione di ATP mitocondriale, rispetto a cellule non trattate; tuttavia, l'effetto del clotrimazolo sulla produzione di ATP era meno evidente rispetto alla diminuzione causata dall'espressione di FAD-PS2. Questo significa che, anche se il distacco di HK1 dai mitocondri svolge un ruolo importante nel determinare i difetti mitocondriali osservati in seguito a espressione di FAD-PS2, la disfunzione nell’omeostasi del Ca2+, descritta in precedenza, contribuisce anch’essa alla diminuzione complessiva dell’attività mitocondriale. Questi risultati sono stati confermati anche con un approccio genetico. Abbiamo abbattuto l'espressione di HK1 endogena, mediante specifici siRNAs e abbiamo sovra-espresso la forma intera di HK1 (FL-HK1) o la forma tronca di HK1 (Tr-HK1), proteina ques’ultima che manca del dominio di legame mitocondriale ma che presenta ancora l'attività catalitica. Il silenziamento della proteina endogena causa una notevole riduzione nella produzione di ATP mitocondriale; la ri-espressione di FL-HK1 è in grado di recuperare completamente il difetto nella produzione di ATP, mentre quella di Tr-HK1 no. Questi risultati confermano nuovamente che il distacco di HK1 dai mitocondri è coinvolto nella manifestazione dei difetti mitocondriali osservati in seguito all’espressione di FAD-PS2. Relativamente a HK1 e al suo ruolo nella regolazione della permeabilità mitocondriale ai substrati, in cellule esprimenti PS2 è stato misurato un aumento nella quantità di piruvato nel citoplasma . È importante notare come il blocco farmacologico della proteina responsabile del trasporto del piruvato all’interno del mitocondrio (MPC) con due diversi farmaci, UK5099 e Pioglitazone, annulli le differenze tra le cellule esprimenti FAD-PS2 e i controlli, indicando che l'espressione di FAD-PS2 agisce anche su questa via metabolica.
In questo lavoro, abbiamo mostrato che forme mutate di PS2 legate a FAD diminuiscono i livelli cellulari di ATP, in particolare la produzione di ATP mitocondriale, con due diversi meccanismi: 1) causando una deregolazione dell’omeostasi del Ca2+, principalmente diminuendo il contenuto di Ca2+ nel RE, e quindi il conseguente ingresso di Ca2+ nel mitocondrio; 2) inducendo il distacco di HK1 dai mitocondri, influenzando così la disponibilità di substrati (per es., piruvato) per i mitocondri. Ulteriori esperimenti saranno finalizzati a: i) valutare l'impatto dell’aumento della vicinanza tra RE e mitocondri causato dall’espressione di PS2 sui difetti mitocondriali riportati; ii) definire il meccanismo molecolare attraverso il quale FAD-PS2 induce il distacco di HK1 dai mitocondri; iii) valutare l’eventuale impatto di queste alterazioni nella progressione del fenotipo AD.

EPrint type:Ph.D. thesis
Tutor:Pizzo, Paola
Ph.D. course:Ciclo 30 > Corsi 30 > SCIENZE BIOMEDICHE SPERIMENTALI
Data di deposito della tesi:09 January 2018
Anno di Pubblicazione:09 January 2018
Key Words:Malattia di Alzheimer, Presenilina2, bioenergetica mitocondrial, esochinasi, calcio. Alzheimer's Disease, Presenilin2, mitochondrial bioenergetics, hexokinase, calcium
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/04 Patologia generale
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:10599
Depositato il:15 Nov 2018 12:51
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