Abnormal glycogen storage in tuberous sclerosis complex caused by impairment of mTORC1-dependent and -independent...

Area of Science:

• Biochemistry
• Cell Biology
• Genetics

Background:

• Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by tumor formation in multiple organs.
• TSC arises from inactivating mutations in TSC1/2 genes, which negatively regulate the mammalian target of rapamycin complex 1 (mTORC1).
• Diminished TSC function is linked to excess glycogen storage, but the underlying mechanism remains unclear.

Purpose of the Study:

• To elucidate the mechanism by which TSC dysfunction leads to abnormal glycogen storage.
• To investigate the roles of mTORC1, GSK3β, and autophagy in TSC-associated glycogen accumulation.
• To identify potential therapeutic targets beyond mTORC1 for TSC.

Main Methods:

• Analysis of human and mouse cells with defective or absent TSC2.
• Assessment of glycogen synthesis, mTORC1 activity, and GSK3β phosphorylation.
• Investigation of lysosomal function and autophagy-related protein degradation (LC3, LAMP1/2).
• Pharmacological inhibition of mTORC1 and Akt pathways.

Main Results:

• Complete TSC2 loss increases glycogen synthesis via mTORC1 hyperactivation and GSK3β inactivation.
• Specific TSC2 mutations elevate glycogen without altering mTORC1 or GSK3β activity.
• mTORC1-independent lysosomal depletion and impaired autophagy drive abnormal glycogen storage in TSC.
• Defective autophagic degradation of glycogen involves abnormal ubiquitination and degradation of autophagy-lysosome proteins.
• Combined mTORC1 and Akt inhibition restored autophagic degradation of glycogen.

Conclusions:

• Abnormal glycogen storage in TSC is driven by mTORC1-independent lysosomal and autophagy defects.
• These findings highlight novel therapeutic targets for TSC beyond the central role of mTORC1.
• Targeting mTORC1-independent pathways is crucial for developing comprehensive TSC treatments.