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Pegoraro, Valentina (2016) MicroRNA e molecole proteiche come biomarcatori dei sottotipi clinici di SLA. [Tesi di dottorato]

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Abstract (inglese)

Background: Amyotrophic lateral sclerosis (ALS) is a rare, progressive, neurodegenerative disorder caused by degeneration of upper and lower motoneuron. The disease process leads to progressive muscle atrophy, weakness, fasciculations and spasticity. About two-thirds of ALS patients have a spinal form of the disease (spinal ALS), which involves the limbs. The spinal ALS has an upper or lower limb onset that starts with weakness and muscle atrophy in hands or feet whereas one-thirds of patients have a bulbar onset (bulbar ALS) usually presenting with dysarthria and dysphagia. The spinal ALS leads to death after 3-5 years from onset while the bulbar ALS die about after 2-3 years from onset. Incidence and prevalence of ALS are higher in men than in women. Male e female gender influences the clinical features of the disease: man have a greater likelihood spinal regions onset whereas women have onset at an older age. The effects of physical exercise and rehabilitation in patients with ALS are still debated: if a patient is inactive, the loss of exercise or muscle training leads to muscle atrophy and disuse that contribute to deterioration in addition to the weakness and muscle atrophy caused by denervation.
MicroRNAs (miRNAs) are small non-coding RNA molecules (19-24 nucleotides), highly conserved, which regulate genes expression at the post transcriptional level. The up-regulation of a specific miRNA determines decreasing expression of the corresponding protein product.
Aim: The aim of this work is the identification of new molecular and biochemical biomarkers to facilitate the study of the various subtypes of ALS. We will study if they provide information on the onset and severity of disease and they might be used as indicators of a therapeutic response in rehabilitation. We will investigate the levels of both muscle-specific (myomiRNAs) and inflammatory/angiogenic microRNAs and other molecular signatures (Myostatin, Follistatin). MicroRNAs will be analized and compared with morphometric study in muscle biopsies of ALS patient and controls. In serum, we will investigate the difference between spinal and bulbar ALS whereas, in muscle we will analyze the difference between male and female patients and in the effect of different age of onset of the disease on microRNAs.
Methods: In 14 ALS patients (10 spinal and 4 bulbar) we measure the serum levels of muscle-specific miR-1, miR-206, miR-133a/b, miR-27a and the inflammatory miRNAs miR-155, miR-146a, miR-221 and miR-149*, and the expression of Myostatin and Follistatin, which are two antagonist regulator of the muscle growth. Morphometric analysis of muscle fiber size is done to correlate muscle atrophy with biochemical-molecular parameters. In 16 muscles ALS biopsies (9 male and 7 female) we analyze the levels of myomiRNAs and inflammatory miRNAs. The circulating levels of myomiRNAs are analysed also in 12 ALS patients (8 male and 4 female) after rehabilitation treatment of 8 weeks in IRCCS San Camillo (Venice).
Results: In ALS patients the expression of serum miR-206 and miR-133 is significantly (p<0.005) increased and miR-27a is significantly (p<0.005) reduced compared to control, also the miRNA profile is significantly higher between spinal versus bulbar ALS. Myostatin/Follistatin ratio was significantly higher in ALS versus control and are higher in bulbar versus spinal ALS. Bulbar ALS patients present more pronounced muscle atrophy than spinal ALS, as documented by our muscle fiber morphometric analysis. In patients ALS biopsy all miRNAs we measured are strongly up-regulated in ALS patients versus control, with the exception of miR-149*. A strong up-regulation (p<0.0001) of all miRNAs is present in male versus female ALS biopsies and in group of ALS patients with age of onset below 55 versus the group of older patients. In serum after 8 weeks of rehabilitation myomiRNAs result down-regulated indicating an active proliferation of satellite cells in muscle and increased neuromuscular junctions.
Conclusion: Muscle mass regulators are particularly down-expressed in bulbar ALS, suggesting a more rapid and diffuse muscle atrophic process. Similar results were obtained on Myostatin/Follistatin ratio. The differences in this regulators between clinical subgroups of ALS patients, in serum and in muscle, may suggest a possible differential role of miRNAs in the pathogenetic accurance of muscle atrophy in motoneurons disease. Furthermore our data suggest that miRNAs are good indicators of muscle recovery in response to rehabilitation conducted for eight weeks consisting of aerobic exercise.

Abstract (italiano)

Background: La SLA è una malattia rara, neurodegenerativa che colpisce i motoneuroni del midollo spinale, del tronco e della corteccia motoria. La perdita dei motoneuroni porta ad atrofia muscolare, debolezza muscolare, fascicolazioni e spasticità. Circa due terzi dei pazienti con SLA presentano una forma spinale della malattia che comincia sia dagli arti superiori che inferiori e sintomi associati a stanchezza con atrofia muscolare. Un terzo dei pazienti presentano un esordio bulbare della malattia che si manifesta inizialmente con disartria e disfagia per solidi e liquidi (paralisi bulbare progressiva). Nella maggior parte dei casi la forma spinale porta a decesso dopo 3-5 anni mentre la paralisi bulbare dopo una media di 2-3 anni. L'incidenza della SLA è riportata maggiore negli uomini che nelle donne. Il sesso influenza alcune caratteristiche fenotipiche della malattia tra cui l'età e il sito d'esordio e alcune caratteristiche cliniche. Gli effetti dell'esercizio fisico e della riabilitazione in pazienti affetti da SLA sono ancora dibattuti: se un paziente è inattivo, la perdita di allenamento e il disuso portano all’atrofia muscolare, che si va a sommare alla debolezza e all'atrofia muscolare causata dalla denervazione e dalla degenerazione dei motoneuroni. I microRNA (miRNA) sono piccole molecole di RNA (19-24 nucleotidi) a singolo filamento, non codificanti, altamente conservati nel corso dell'evoluzione che regolano finemente l'espressione genica a livello post-trascrizionale. L’up-regolazione di uno specifico microRNA determina un decremento dell’espressione del prodotto proteico corrispondente.
Scopo: L'obiettivo di questo lavoro è l’identificazione di nuovi biomarcatori molecolari e biochimici che facilitino lo studio dei vari sottotipi di SLA, che diano informazioni su insorgenza e gravità di malattia e che possano essere utilizzati come indicatori di risposta in trials clinico-riabilitativi. Abbiamo studiato i livelli di espressione dei miRNA muscolo-specifici e infiammatori/angiogenici e altre molecole proteiche (Miostatina/Follistatina). L’analisi dei miRNA è stata comparata con la morfometria delle fibre muscolari. Nel siero, in particolare, abbiamo indagato le differenze tra pazienti ad esordio spinale e pazienti ad esordio bulbare mentre, nel muscolo, abbiamo analizzato le differenze tra maschi e femmine e tra pazienti con diversa età d'esordio.
Metodi: In 14 pazienti SLA (10 spinali e 4 bulbari) abbiamo misurato i livelli sierici dei miRNA muscolo-specifici miR-1, miR-206, miR-133a/b, miR-27a e dei miRNA infiammatori miR-155, miR-146a, miR-221 e miR-149* e l'espressione della Miostatina e della Follistatina, due fattori regolatori antagonisti della crescita muscolare. L'analisi morfometrica delle fibre è stata correlata all'atrofia muscolare misurata con parametri biochimici molecolari. In 16 biopsie muscolari di pazienti SLA (9 maschi e 7 femmine) sono stati analizzati i livelli dei myomiRNA e dei miRNA infiammatori. I livelli circolanti dei myomiRNA sono stati analizzati anche in 12 pazienti SLA (8 maschi e 4 femmine) dopo trattamento riabilitativo di 8 settimane.
Risultati: Nei pazienti SLA c'è un incremento significativo (p<0.005) dei livelli sierici del miR-206, miR-133 mentre il miR-27a è significativamente (p<0.005) ridotto confrontato con i controlli e anche tra pazienti spinali e bulbari. Il rapporto Miostatina/Follistatina risulta più alto nei pazienti SLA rispetto ai controlli, simili dati si riscontrano in pazienti SLA ad esordio bulbare rispetto a pazienti con esordio spinale. I pazienti con SLA bulbare presentano un grado più alto di atrofia muscolare rispetto ai pazienti con SLA spinale documentato dall'analisi morfometrica delle fibre. Nelle biopsie muscolari di pazienti SLA tutti i miRNA presi in esame risultano fortemente up-regolati (p<0.0001) nei pazienti rispetto ai controlli ad eccezione del miR-149*. Vi è una up-regolazione significativa (p<0.0001) di tutti i miRNA nei maschi rispetto alle femmine e nei pazienti con una età d'esordio sotto i 55 anni rispetto al gruppo di pazienti più vecchi. Dopo 8 settimane di riabilitazione tutti i myomiRNA risultano down-regolati.
Conclusioni: I microRNA e altre molecole proteiche (Miostatina/Follistatina) risultano particolarmente down-regolati nei pazienti con SLA bulbare, suggerendo così il risultato di un processo atrofico muscolare più rapido e diffuso. Le differenze osservate nei sottogruppi di pazienti SLA, nel siero e nelle biopsie muscolari, potrebbero suggerire un possibile ruolo differenziale dei miRNA negli eventi patogenetici della malattia dei motoneuroni. Inoltre i nostri dati suggeriscono che i myomiRNA rappresentano possibili indicatori di recupero muscolare in risposta alla riabilitazione.

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Tipo di EPrint:Tesi di dottorato
Relatore:Corrado , Angelini
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > NEUROSCIENZE
Data di deposito della tesi:28 Gennaio 2016
Anno di Pubblicazione:28 Gennaio 2016
Parole chiave (italiano / inglese):microRNA/miRNA, SLA/ALS, Miostatina/Miostatin, Follistatina/Follistatin
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:9312
Depositato il:21 Ott 2016 15:13
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