title: Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration.
abstract: Tuberous sclerosis complex (TSC) is a neurogenetic disorder that often causes brain abnormalities leading to epilepsy, developmental delay, and autism. TSC is caused by inactivating mutations in either of the genes encoding the proteins hamartin (TSC1) and tuberin (TSC2). These proteins form a heterodimer that inhibits the mammalian target of rapamycin complex 1 (mTORC1) pathway, controlling translation and cell growth. Loss of either protein results in dysregulated mTORC1 activation, an important aspect of TSC pathogenesis. About thirty percent of TSC patients have cerebellar pathology that is poorly understood. To investigate the effects of TSC on the cerebellum, we created a mouse model in which the Tsc2 gene was selectively deleted from Purkinje cells starting at postnatal day 6 (P6). The loss of Tsc2 caused a progressive increase in Purkinje cell size and subsequent death from apoptosis. Purkinje cell loss was predominantly cell type specific and associated with motor deficits. Immunohistochemical analysis showed that both endoplasmic reticulum (ER) and oxidative stress were increased in Tsc2-null Purkinje cells. The cell death and ER stress phenotypes were rescued by treatment with the mTORC1 inhibitor rapamycin. To assess whether the murine Purkinje cell loss has a correlate to the human TSC, we analyzed postmortem cerebellum samples from TSC patients and detected Purkinje cell loss in half of the samples. Our results establish a critical role for the TSC complex in Purkinje cell survival by regulating ER and oxidative stress and reveal a novel aspect of TSC neuropathology.
authors.affiliation: University of Texas Health Science Center at Houston, Department of Pediatrics, Division of Medical Genetics, Houston, TX 77030, USA.
authors.forename: R Michelle
authors.initials: RM
authors.lastname: Reith
authors.forename: Sharon
authors.initials: S
authors.lastname: Way
authors.forename: James
authors.initials: J
authors.lastname: McKenna
authors.forename: Katherine
authors.initials: K
authors.lastname: Haines
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gambello
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D048429:Cell Size; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology*; D014402:Tuberous Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins