ArticleNeurobiology of disease2011
Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration.
Article in Neurobiology of disease, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 1 of them a synthesis that pooled it.
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Who cites it
38 citing papers in PubMed, 1 synthesis or guideline pooled it.
- The prevalence of autism in cerebellar malformations: a systematic review and meta-analysis.Journal of neurodevelopmental disorders · 2026Pooled it
- Incidence and Characteristics of Cerebellar Atrophy/Volume Loss in Children with Confirmed Diagnosis of Tuberous Sclerosis Complex.Children (Basel, Switzerland) · 2024Article
- The Cerebellar Involvement in Autism Spectrum Disorders: From the Social Brain to Mouse Models.International journal of molecular sciences · 2022Review
- Neonatal GALT gene replacement offers metabolic and phenotypic correction through early adulthood in a rat model of classic galactosemia.Journal of inherited metabolic disease · 2022Article
- Association of Oxidative Stress with Neurological Disorders.Current neuropharmacology · 2022Article
- Harnessing rare variants in neuropsychiatric and neurodevelopment disorders-a Keystone Symposia report.Annals of the New York Academy of Sciences · 2021Review
- Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model.Brain, behavior, & immunity - health · 2021Article
- Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations.Neuropathology and applied neurobiology · 2020Article
- Ornithine decarboxylase, the rate-limiting enzyme of polyamine synthesis, modifies brain pathology in a mouse model of tuberous sclerosis complex.Human molecular genetics · 2020Article
- Autophagy in Rare (NonLysosomal) Neurodegenerative Diseases.Journal of molecular biology · 2020Review
- Novel mTORC1 Mechanism Suggests Therapeutic Targets for COMPopathies.The American journal of pathology · 2019Article
- Sensitive Periods for Cerebellar-Mediated Autistic-like Behaviors.Cell reports · 2018Article
- Decreased rates of cerebral protein synthesis measured in vivo in a mouse model of Tuberous Sclerosis Complex: unexpected consequences of reduced tuberin.Journal of neurochemistry · 2018Article
- Cerebellar volume as an imaging marker of development in infants with tuberous sclerosis complex.Neurology · 2018Article
- Time-resolved analysis of amino acid stress identifies eIF2 phosphorylation as necessary to inhibit mTORC1 activity in liver.The Journal of biological chemistry · 2018Article
- Imaging genetics in neurodevelopmental psychopathology.American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics · 2017Review
- Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders.British journal of clinical pharmacology · 2016Review
- Lessons learned from studying syndromic autism spectrum disorders.Nature neuroscience · 2016Review
- The Role of the Pediatric Cerebellum in Motor Functions, Cognition, and Behavior: A Clinical Perspective.Neuroimaging clinics of North America · 2016Review
- Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2016Article
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Authors and funding
5 authors.
Funding
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.
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