glycogen and Tuberous-Sclerosis

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that causes tumor formation in multiple organs. TSC is caused by inactivating mutations in the genes encoding TSC1/2, negative regulators of the mammalian target of rapamycin complex 1 (mTORC1). Diminished TSC function is associated with excess glycogen storage, but the causative mechanism is unknown. By studying human and mouse cells with defective or absent TSC2, we show that complete loss of TSC2 causes an increase in glycogen synthesis through mTORC1 hyperactivation and subsequent inactivation of glycogen synthase kinase 3β (GSK3β), a negative regulator of glycogen synthesis. Specific TSC2 pathogenic mutations, however, result in elevated glycogen levels with no changes in mTORC1 or GSK3β activities. We identify mTORC1-independent lysosomal depletion and impairment of autophagy as the driving causes underlying abnormal glycogen storage in TSC irrespective of the underlying mutation. The defective autophagic degradation of glycogen is associated with abnormal ubiquitination and degradation of essential proteins of the autophagy-lysosome pathway, such as LC3 and lysosomal associated membrane protein 1 and 2 (LAMP1/2) and is restored by the combined use of mTORC1 and Akt pharmacological inhibitors. In complementation to current models that place mTORC1 as the central therapeutic target for TSC pathogenesis, our findings identify mTORC1-independent pathways that are dysregulated in TSC and that should therefore be taken into account in the development of a therapeutic treatment.

Topics: Animals; Autophagy; Glycogen; Glycogen Synthase Kinase 3 beta; Humans; Lysosomal-Associated Membrane Protein 1; Lysosomal-Associated Membrane Protein 2; Lysosomes; Mechanistic Target of Rapamycin Complex 1; Mice; Mutation; Proteolysis; Signal Transduction; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Ubiquitination

Tuberous sclerosis is a hamartoma syndrome due to mutations in TSC1 or TSC2 in which cardiac rhabdomyomas are seen in approximately 60% of patients. These lesions have an unusual natural history as they are usually most prominent immediately after birth and spontaneously resolve in most cases. To develop a mouse model of this lesion, we used a conditional, floxed allele of Tsc1 and a modified myosin light chain 2v allele in which cre recombinase expression occurs in ventricular myocytes. Mice with ventricular loss of Tsc1 had a median survival of 6 months and developed a dilated cardiomyopathy with the occurrence of scattered foci of enlarged ventricular myocytes. The enlarged cells were periodic acid-Schiff positive indicating the presence of excess glycogen and expressed elevated levels of phospho-S6, similar to findings in patient rhabdomyoma cells. The observations confirm that rhabdomyomas occur through a two hit mechanism of pathogenesis. However, the mice showed no evidence of fetal/neonatal demise, and there was no evidence of proliferation in the lesions. We propose that these differences are due to the timing of loss of Tsc1 in the ventricular myocytes and/or the truncated gestational period in the mouse compared with humans, during which progestational hormones may accentuate the growth of patient rhabdomyomas.

Topics: Alleles; Animals; Cardiac Myosins; Cell Proliferation; Glycogen; Heart Neoplasms; Heart Ventricles; Integrases; Mice; Muscle Cells; Mutation; Myocardium; Myosin Light Chains; Phosphorylation; Rhabdomyoma; Ribosomal Protein S6 Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins

Electron microscopic study of bilateral renal angiomyolipoma in a case of tuberous sclerosis showed two cell types: smooth muscle cells and fibroblasts. There were no tubular or glomerular elements within the tumor mass. To our knowledge this study represents the first ultrastructural demonstration of smooth muscle cells occurring in the renal lesions of this complex.

Topics: Adult; Basement Membrane; Cytoplasmic Granules; Glycogen; Humans; Kidney Neoplasms; Male; Muscle, Smooth; Tuberous Sclerosis

Topics: Astrocytoma; Brain Neoplasms; Caudate Nucleus; Cell Nucleus; Child; Endoplasmic Reticulum; Female; Glycogen; Golgi Apparatus; Humans; Inclusion Bodies; Microscopy, Electron; Ribosomes; Tuberous Sclerosis

Topics: Adolescent; Biopsy; Brain Chemistry; Cerebral Cortex; Frontal Lobe; Glycogen; Humans; Male; Microscopy, Electron; Necrosis; Neuroglia; Neurons; Synapses; Tuberous Sclerosis

Topics: Astrocytoma; Brain Neoplasms; Ependymoma; Ganglioneuroma; Glioblastoma; Glycogen; Histocytochemistry; Humans; Medulloblastoma; Neurilemmoma; Oligodendroglioma; Papilloma; Tuberous Sclerosis

Topics: Endocardial Fibroelastosis; Glycogen; Glycogen Storage Disease; Heart; Humans; Medical Records; Myocardium; Tuberous Sclerosis