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  • 1
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    Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-07-06
    Description: Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology and correlate cerebellar pathology with increased ASD symptomatology. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615424/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615424/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsai, Peter T -- Hull, Court -- Chu, YunXiang -- Greene-Colozzi, Emily -- Sadowski, Abbey R -- Leech, Jarrett M -- Steinberg, Jason -- Crawley, Jacqueline N -- Regehr, Wade G -- Sahin, Mustafa -- K12 NS079414/NS/NINDS NIH HHS/ -- P30HD18655/HD/NICHD NIH HHS/ -- R01 NS032405/NS/NINDS NIH HHS/ -- R01NS032405/NS/NINDS NIH HHS/ -- R01NS58956/NS/NINDS NIH HHS/ -- T32 MH020017/MH/NIMH NIH HHS/ -- T32 NS007473/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2012 Aug 30;488(7413):647-51. doi: 10.1038/nature11310.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. peter.tsai@childrens.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763451" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/complications/genetics/pathology/*physiopathology ; Behavior, Animal/drug effects ; Cell Count ; Cell Shape/drug effects ; Cerebellum/drug effects/pathology/*physiopathology ; Grooming/drug effects/physiology ; Heterozygote ; Maze Learning/drug effects/physiology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mutation/genetics ; Purkinje Cells/drug effects/*metabolism ; Rotarod Performance Test ; Sirolimus/pharmacology ; Synapses/metabolism ; TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Tuberous Sclerosis/complications/genetics ; Tumor Suppressor Proteins/deficiency/*genetics/*metabolism ; Vocalization, Animal/drug effects/physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioral features (2012)
    Oxford University Press
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    Publication Date: 2012-09-14
    Description: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with prominent brain manifestations due to mutations in either TSC1 or TSC2 . Here, we describe novel mouse brain models of TSC generated using conditional hypomorphic and null alleles of Tsc2 combined with the neuron-specific synapsin I cre ( SynIcre ) allele. This allelic series of homozygous conditional hypomorphic alleles ( Tsc2 c-del3/c-del3 SynICre + ) and heterozygote null/conditional hypomorphic alleles ( Tsc2 k/c-del3 SynICre + ) achieves a graded reduction in expression of Tsc2 in neurons in vivo . The mice demonstrate a progressive neurologic phenotype including hunchback, hind limb clasp, reduced survival and brain and cortical neuron enlargement that correlates with a graded reduction in expression of Tsc2 in the two sets of mice. Both models also showed behavioral abnormalities in anxiety, social interaction and learning assays, which correlated with Tsc2 protein levels as well. The observations demonstrate that there are graded biochemical, cellular and clinical/behavioral effects that are proportional to the extent of reduction in Tsc2 expression in neurons. Further, they suggest that some patients with milder manifestations of TSC may be due to persistent low-level expression of functional protein from their mutant allele. In addition, they point to the potential clinical benefit of strategies to raise TSC2 protein expression from the wild-type allele by even modest amounts.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 3
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    Obesity accelerates epigenetic aging [Medical Sciences] (2014)
    National Academy of Sciences
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    Publication Date: 2014-10-29
    Description: Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. Here we use a novel epigenetic biomarker of aging (referred to as an “epigenetic clock”) to study the relationship between high body mass index (BMI) and the DNA methylation...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1 (2014)
    Oxford University Press
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    Publication Date: 2014-06-21
    Description: Tuberous sclerosis complex (TSC) is a disorder arising from mutation in the TSC1 or TSC2 gene, characterized by the development of hamartomas in various organs and neurological manifestations including epilepsy, intellectual disability and autism. TSC1/2 protein complex negatively regulates the mammalian target of rapamycin complex 1 (mTORC1) a master regulator of protein synthesis, cell growth and autophagy. Autophagy is a cellular quality-control process that sequesters cytosolic material in double membrane vesicles called autophagosomes and degrades it in autolysosomes. Previous studies in dividing cells have shown that mTORC1 blocks autophagy through inhibition of Unc-51-like-kinase1/2 (ULK1/2). Despite the fact that autophagy plays critical roles in neuronal homeostasis, little is known on the regulation of autophagy in neurons. Here we show that unlike in non-neuronal cells, Tsc2 -deficient neurons have increased autolysosome accumulation and autophagic flux despite mTORC1-dependent inhibition of ULK1. Our data demonstrate that loss of Tsc2 results in autophagic activity via AMPK-dependent activation of ULK1. Thus, in Tsc2 -knockdown neurons AMPK activation is the dominant regulator of autophagy. Notably, increased AMPK activity and autophagy activation are also found in the brains of Tsc1- conditional mouse models and in cortical tubers resected from TSC patients. Together, our findings indicate that neuronal Tsc1/2 complex activity is required for the coordinated regulation of autophagy by AMPK. By uncovering the autophagy dysfunction associated with Tsc2 loss in neurons, our work sheds light on a previously uncharacterized cellular mechanism that contributes to altered neuronal homeostasis in TSC disease.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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