Dissecting the oxinflammatory mechanisms involved in Rett Syndrome pre-symptomatic/symptomatic switch: focus on mitochondria and inflammasome activation

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Abstract:

Rett syndrome (RTT) is a genetic neurodevelopmental disorder characterized by progressive regression of mental and psychomotor development (symptomatic phase) after a period of apparent normal growth during the first months of life (presymptomatic phase). Evidence indicates that metabolic abnormalities including mitochondrial dysfunction, aberrant redox homeostasis and subclinical inflammation significantly contribute to RTT. A crosstalk between aberrant redox and immune responses generates a vicious circle of oxinflammatory phenomena involved in disease progression and clinical severity. While many abnormal molecular and cellular aspects of RTT have been fairly delineated in its symptomatic phase, what happens before the onset of symptoms still remains unknown. However, the peculiar pathogenic development of RTT characterized by a relatively slow transition to the symptomatic stage offers a precious time window of opportunity for early diagnosis and intervention. Even more considering that there is no cure for RTT, but only expensive polytherapies with a greater risk of side effects. In addition, to date, no gene therapy has yet been approved. Based on these premises, we intend to identify the chain of molecular events involved in the enigmatic switch from presymptomatic to symptomatic stage of RTT. We believe that early alterations in mitochondrial function/structure associated with abnormal NLRP3 inflammasome activation may play a relevant and active role in the generation of RTT phenotypes, in the brain and peripheral tissues. Given the known difficulties in studying human brain diseases, we plan to take advantage of suitable in vivo, in vitro and ex vivo models of RTT, such as Mecp2-null mouse model, RTT patient iPSCs and serum samples. First, we will focus on characterization of molecular processes involved in mitochondrial dynamics and NLRP3 inflammasome in brain and serum samples from male Mecp2 KO mice, at presymptomatic and symptomatic stage. Using live-cell imaging, similar parameters will be also evaluated in neurons isolated from KO mice at postnatal day 1 and monitored until day in vitro 18. Then, to translate the findings obtained in KO mice to human condition, RTT patient iPSCs, differentiated in both fibroblasts and neurons, will be monitored overtime for the mitochondrial/inflammasome hallmarks related to the presymptomatic/symptomatic switch. To confirm their role in the manifestation of disease-phenotype and to establish correlations between cellular and systemic pathophysiological features of RTT, key mitochondrial/inflammasome biomarkers will be evaluated in serum samples. The accomplishment of this project would help to furthering the understanding of RTT pathophysiology and to rapidly refine extensive preclinical studies to hopefully allow to speed-up the development of innovative therapies aimed to delay the onset of the clinical symptoms of the disease and ameliorate the quality of life of RTT patients.

Dettagli progetto:

Referente scientifico: Valacchi Giuseppe

Fonte di finanziamento: Bando PRIN 2022 

Data di avvio: 18/10/2023

Data di fine: 18/10/2025

Contributo MUR: 102.080 €

Cofinanziamento UniFe: 29.128 €

Partner:

  • Politecnico di FERRARA  (capofila)
  • Università degli Studi di TRIESTE