title: 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.
authors.affiliation: Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miyahara
authors.forename: Manabu
authors.initials: M
authors.lastname: Natsumeda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aoki
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Toyoshima
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zheng
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takeuchi
authors.forename: Hiroatsu
authors.initials: H
authors.lastname: Murakami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masuda
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kameyama
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Izumi
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Fujii
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001343:Autophagy / Q000502:physiology*; D001344:Autopsy; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D015225:Magnetoencephalography; D008297:Male; D016253:Microscopy, Immunoelectron; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics*; D015899:Tomography, Emission-Computed, Single-Photon; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000601:surgery; D055815:Young Adult
chemical_list: C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins