| Popis: |
Autophagy is a lysosomal pathway deputed to the recycling of cellular components. Regulation of autophagy is essential for tissue homeostasis. The mTORC1 kinase tunes autophagy according to nutrient levels and environmental factors. Recently the laboratory in which I performed the experiments used for my thesis has demonstrated that autophagy, by controlling collagen secretion in chondrocytes, is necessary during bone growth. However, whether mTORC1 and autophagy play any role in the pathogenesis of skeletal disorders is still unknown. In this thesis work I show that an altered mTORC1 signaling impairs autophagy and consequently bone growth in lysosomal storage disorders (LSDs). I found that in LSD chondrocytes a proteasome-sensitive increase of mTORC1 signaling inhibits late steps of autophagy through the phosphorylation of the UV radiation resistance-associated gene (UVRAG) protein, a member of the Beclin1/Vps34 complex. Reducing mTORC1 signaling or enhancing Beclin1/Vps34/UVRAG complex activity rescued autophagy flux in LSD chondrocytes. In vivo, normalization of mTORC1 signaling or pharmacological induction of Beclin1 rescued collagen levels in cartilage and bone growth in two different LSD mouse models. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest their modulation as new therapy for the skeletal abnormalities observed in LSDs. |
