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Suppressed expression of autophagosomal protein LC3 in cortical tubers of tuberous sclerosis complex.

ABSTRACT: Tuberous sclerosis complex (TSC) is characterized by benign tumors and hamartomas, including cortical tubers. Hamartin and tuberin, encoded by the TSC 1 and 2 genes, respectively, constitute a functional complex that negatively regulates the mammalian target of rapamycin (mTOR) signaling pathway, eventually promoting the induction of autophagy. In the present study, we assessed the induction of autophagy in cortical tubers surgically removed from seven patients with TSC in comparison with five controls of cortical tissue taken from non-TSC patients with epilepsy. Immunoblotting demonstrated a marked reduction of LC3B-I and LC3B-II in tubers relative to the controls. In tubers, strong, diffuse and dot-like immunoreactivity (IR) for LC3B was observed in dysmorphic neurons and balloon cells, but LC3B-IR in other neurons with normal morphology was significantly weaker than that in neurons in the controls. Immunoelectron microscopy revealed diffuse distribution of LC3B-IR within the cytoplasm of balloon cells. The dot-like pattern may correspond to abnormal aggregation bodies involving LC3. In an autopsy patient with TSC, we observed that LC3B-IR in neurons located outside of the tubers was preserved. Thus, autophagy is suppressed in tubers presumably through the mTOR pathway, and possibly a pathological autophagy reaction occurs in the dysmorphic neurons and balloon cells.

SUBMITTER: Miyahara H

PROVIDER: S-EPMC8029364 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Suppressed expression of autophagosomal protein LC3 in cortical tubers of tuberous sclerosis complex.

Miyahara Hiroaki H Natsumeda Manabu M Shiga Atsushi A Aoki Hiroshi H Toyoshima Yasuko Y Zheng Yingjun Y Takeuchi Ryoko R Murakami Hiroatsu H Masuda Hiroshi H Kameyama Shigeki S Izumi Tatsuro T Fujii Yukihiko Y Takahashi Hitoshi H Kakita Akiyoshi A

Brain pathology (Zurich, Switzerland) 20121023 3

Tuberous sclerosis complex (TSC) is characterized by benign tumors and hamartomas, including cortical tubers. Hamartin and tuberin, encoded by the TSC 1 and 2 genes, respectively, constitute a functional complex that negatively regulates the mammalian target of rapamycin (mTOR) signaling pathway, eventually promoting the induction of autophagy. In the present study, we assessed the induction of autophagy in cortical tubers surgically removed from seven patients with TSC in comparison with five c ...[more]

PMID: 22974335

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Project description:Introduction and importance Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations in TSC1 or TSC2 genes, resulting in benign lesions that involve multiple organs including the central nerves system. Case presentation A 39-year-old male of known TSC presented with inability to walk for two months. On physical examination, he was consciously oriented and cooperative, but he had spastic tetraparesis in the muscle-motor examination. On brain imaging, cystic lesions of various sizes in the supra and infratentorial regions were observed, consistent with giant cyst-like tubers. However, they could not differentiate from TSC related brain tumors based on the imaging findings. He underwent surgical intervention to resect/evacuate the large cystic lesion, which had the mass effects on the brain stem. The pathologic examinations revealed no malignant changes. Clinical discussion Although the cyst-like lesions in the cortex and white matter have been reported in several previous studies of TSC, they usually had a small size and similar intensity to CSF on T2- weighted MRI and low intensity on FLAIR images. Conclusion Giant cyst-like cortical tubers are exceedingly rare and atypical findings of tuberous sclerosis complex, which are usually associated with epilepsy and neurological deficits. Though many authors recommend the brain MRI as a screening tool for patients with TSC once every 1–3 years until the age of 25, our report showed that the brain lesions may develop in patients with TSC even after the age of 25. Thus, the MRI should be used periodically in all patients with TSC to timely detect the brain lesions and prevent the patient's disability. Surgical resection is the mainstay of treatment for the symptomatic cystic-like cortical tuber; however, it may recur after resection. Highlights • Giant cyst-like cortical tubers are rare and atypical findings of tuberous sclerosis complex.• They are usually associated with epilepsy and neurological deficits.• MRI should be used periodically in all patients with tuberous sclerosis complex to timely detect the brain lesions.• Surgical resection is the mainstay of treatment. However, these lesions may recur after resection.

Project description:Tuberous sclerosis complex (TSC) is characterized by hamartomatous lesions in various organs and arises due to mutations in the TSC1 or TSC2 genes. TSC mutations lead to a range of neurological manifestations including epilepsy, cognitive impairment, autism spectrum disorders (ASD), and brain lesions that include cortical tubers. There is evidence that seizures arise at or near cortical tubers, but it is unknown why some tubers are epileptogenic while others are not. We have previously reported increased tryptophan metabolism measured with α[11C]-methyl-l-tryptophan (AMT) positron emission tomography (PET) in epileptogenic tubers in approximately two-thirds of patients with tuberous sclerosis and intractable epilepsy. However, the underlying mechanisms leading to seizure onset in TSC remain poorly characterized. MicroRNAs are enriched in the brain and play important roles in neurodevelopment and brain function. Recent reports have shown aberrant microRNA expression in epilepsy and TSC. In this study, we performed microRNA expression profiling in brain specimens obtained from TSC patients undergoing epilepsy surgery for intractable epilepsy. Typically, in these resections several non-seizure onset tubers are resected together with the seizure-onset tubers because of their proximity. We directly compared seizure onset tubers, with and without increased tryptophan metabolism measured with PET, and non-onset tubers to assess the role of microRNAs in epileptogenesis associated with these lesions. Whether a particular tuber was epileptogenic or non-epileptogenic was determined with intracranial electrocorticography, and tryptophan metabolism was measured with AMT PET. We identified a set of five microRNAs (miR-142-3p, 142-5p, 223-3p, 200b-3p and 32-5p) that collectively distinguish among the three primary groups of tubers: non-onset/AMT-cold (NC), onset/AMT-cold (OC), and onset/AMT-hot (OH). These microRNAs were significantly upregulated in OH tubers compared to the other two groups, and microRNA expression was most significantly associated with AMT-PET uptake. The microRNAs target a group of genes enriched for synaptic signaling and epilepsy risk, including SLC12A5, SYT1, GRIN2A, GRIN2B, KCNB1, SCN2A, TSC1, and MEF2C. We confirmed the interaction between miR-32-5p and SLC12A5 using a luciferase reporter assay. Our findings provide a new avenue for subsequent mechanistic studies of tuber epileptogenesis in TSC.

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Suppressed expression of autophagosomal protein LC3 in cortical tubers of tuberous sclerosis complex.

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Suppressed expression of autophagosomal protein LC3 in cortical tubers of tuberous sclerosis complex.

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