Cerebral Cavernous Malformation (CCM) is a major cerebrovascular disease of genetic origin affecting 0.3-0.5% of the population and characterized by abnormally enlarged and leaky capillaries that predispose to seizures, neurological deficits and intracerebral hemorrhage. It occurs sporadically or is dominantly inherited with incomplete penetrance and variable expressivity. Three disease genes have been identified: KRIT1 (CCM1), CCM2 and CCM3; however, pharmacological treatment is not yet available. Previously, we demonstrated that KRIT1 plays a major role in modulating master regulators of ROS homeostasis and cell responses to oxidative stress, including FoxO1, SOD2 and c-Jun, suggesting that altered redox signaling and oxidative stress contribute to CCM pathogenesis. Recently, we found that defective autophagy and enhanced ROS production are common features of CCM gene loss-of-function, and underlie major disease signatures, suggesting a unifying pathogenetic mechanism. Furthermore, we showed the effectiveness of distinct autophagy inducers and antioxidant compounds in rescuing disease phenotypes, and identified genetic modifiers influencing disease severity, including polymorphisms of oxidative stress-related genes. Taken together, our data point to a major role for defective autophagy and altered redox signaling in CCM pathogenesis, and indicate that inter-individual variability in cell responses to oxidative stress may impact disease onset and severity, suggesting novel therapeutic approaches.
Altered redox signaling and oxidative stress: the emerging faces of Cerebral Cavernous Malformation (CCM) pathogenesis
RETTA, Saverio Francesco
2016-01-01
Abstract
Cerebral Cavernous Malformation (CCM) is a major cerebrovascular disease of genetic origin affecting 0.3-0.5% of the population and characterized by abnormally enlarged and leaky capillaries that predispose to seizures, neurological deficits and intracerebral hemorrhage. It occurs sporadically or is dominantly inherited with incomplete penetrance and variable expressivity. Three disease genes have been identified: KRIT1 (CCM1), CCM2 and CCM3; however, pharmacological treatment is not yet available. Previously, we demonstrated that KRIT1 plays a major role in modulating master regulators of ROS homeostasis and cell responses to oxidative stress, including FoxO1, SOD2 and c-Jun, suggesting that altered redox signaling and oxidative stress contribute to CCM pathogenesis. Recently, we found that defective autophagy and enhanced ROS production are common features of CCM gene loss-of-function, and underlie major disease signatures, suggesting a unifying pathogenetic mechanism. Furthermore, we showed the effectiveness of distinct autophagy inducers and antioxidant compounds in rescuing disease phenotypes, and identified genetic modifiers influencing disease severity, including polymorphisms of oxidative stress-related genes. Taken together, our data point to a major role for defective autophagy and altered redox signaling in CCM pathogenesis, and indicate that inter-individual variability in cell responses to oxidative stress may impact disease onset and severity, suggesting novel therapeutic approaches.File | Dimensione | Formato | |
---|---|---|---|
SFRR-E_2016_Abstract_Retta.pdf
Accesso riservato
Descrizione: Abstract
Tipo di file:
POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione
411.54 kB
Formato
Adobe PDF
|
411.54 kB | Adobe PDF | Visualizza/Apri Richiedi una copia |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.