Metabolomic studies identify changes in transmethylation and polyamine metabolism in a brain-specific mouse model of tuberous sclerosis complex

James McKenna, David Kapfhamer, Jason M. Kinchen, Brandi Wasek, Matthew Dunworth, Tracy Murray Stewart, Teodoro Bottiglieri, Robert A Casero, Michael J. Gambello

Research output: Contribution to journalArticle

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and the quintessential disorder of mechanistic Target of Rapamycin Complex 1 (mTORC1) dysregulation. Loss of either causative gene, TSC1 or TSC2, leads to constitutive mTORC1 kinase activation and a pathologically anabolic state of macromolecular biosynthesis. Little is known about the organ-specific metabolic reprogramming that occurs in TSC-affected organs. Using a mouse model of TSC in which Tsc2 is disrupted in radial glial precursors and their neuronal and glial descendants, we performed an unbiased metabolomic analysis of hippocampi to identify Tsc2-dependent metabolic changes. Significant metabolic reprogramming was found in well-established pathways associated with mTORC1 activation, including redox homeostasis, glutamine/tricarboxylic acid cycle, pentose and nucleotide metabolism. Changes in two novel pathways were identified: transmethylation and polyamine metabolism. Changes in transmethylation included reduced methionine, cystathionine, S-adenosylmethionine (SAM-the major methyl donor), reduced SAM/S-adenosylhomocysteine ratio (cellular methylation potential), and elevated betaine, an alternative methyl donor. These changes were associated with alterations in SAM-dependent methylation pathways and expression of the enzymes methionine adenosyltransferase 2A and cystathionine beta synthase. We also found increased levels of the polyamine putrescine due to increased activity of ornithine decarboxylase, the rate-determining enzyme in polyamine synthesis. Treatment of Tsc2+/- mice with the ornithine decarboxylase inhibitor a-difluoromethylornithine, to reduce putrescine synthesis dose-dependently reduced hippocampal astrogliosis. These data establish roles for SAMdependent methylation reactions and polyamine metabolismin TSC neuropathology. Importantly, both pathways are amenable to nutritional or pharmacologic therapy.

Original languageEnglish (US)
Pages (from-to)2113-2124
Number of pages12
JournalHuman Molecular Genetics
Volume27
Issue number12
DOIs
StatePublished - Jun 15 2018

Fingerprint

Tuberous Sclerosis
Metabolomics
Polyamines
Methylation
Putrescine
Brain
Neuroglia
Methionine Adenosyltransferase
S-Adenosylhomocysteine
Cystathionine
Cystathionine beta-Synthase
Eflornithine
Pentoses
S-Adenosylmethionine
Betaine
Ornithine Decarboxylase
Citric Acid Cycle
Enzymes
Glutamine
Methionine

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Metabolomic studies identify changes in transmethylation and polyamine metabolism in a brain-specific mouse model of tuberous sclerosis complex. / McKenna, James; Kapfhamer, David; Kinchen, Jason M.; Wasek, Brandi; Dunworth, Matthew; Murray Stewart, Tracy; Bottiglieri, Teodoro; Casero, Robert A; Gambello, Michael J.

In: Human Molecular Genetics, Vol. 27, No. 12, 15.06.2018, p. 2113-2124.

Research output: Contribution to journalArticle

McKenna, James ; Kapfhamer, David ; Kinchen, Jason M. ; Wasek, Brandi ; Dunworth, Matthew ; Murray Stewart, Tracy ; Bottiglieri, Teodoro ; Casero, Robert A ; Gambello, Michael J. / Metabolomic studies identify changes in transmethylation and polyamine metabolism in a brain-specific mouse model of tuberous sclerosis complex. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 12. pp. 2113-2124.
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AU - McKenna, James

AU - Kapfhamer, David

AU - Kinchen, Jason M.

AU - Wasek, Brandi

AU - Dunworth, Matthew

AU - Murray Stewart, Tracy

AU - Bottiglieri, Teodoro

AU - Casero, Robert A

AU - Gambello, Michael J.

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AB - Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and the quintessential disorder of mechanistic Target of Rapamycin Complex 1 (mTORC1) dysregulation. Loss of either causative gene, TSC1 or TSC2, leads to constitutive mTORC1 kinase activation and a pathologically anabolic state of macromolecular biosynthesis. Little is known about the organ-specific metabolic reprogramming that occurs in TSC-affected organs. Using a mouse model of TSC in which Tsc2 is disrupted in radial glial precursors and their neuronal and glial descendants, we performed an unbiased metabolomic analysis of hippocampi to identify Tsc2-dependent metabolic changes. Significant metabolic reprogramming was found in well-established pathways associated with mTORC1 activation, including redox homeostasis, glutamine/tricarboxylic acid cycle, pentose and nucleotide metabolism. Changes in two novel pathways were identified: transmethylation and polyamine metabolism. Changes in transmethylation included reduced methionine, cystathionine, S-adenosylmethionine (SAM-the major methyl donor), reduced SAM/S-adenosylhomocysteine ratio (cellular methylation potential), and elevated betaine, an alternative methyl donor. These changes were associated with alterations in SAM-dependent methylation pathways and expression of the enzymes methionine adenosyltransferase 2A and cystathionine beta synthase. We also found increased levels of the polyamine putrescine due to increased activity of ornithine decarboxylase, the rate-determining enzyme in polyamine synthesis. Treatment of Tsc2+/- mice with the ornithine decarboxylase inhibitor a-difluoromethylornithine, to reduce putrescine synthesis dose-dependently reduced hippocampal astrogliosis. These data establish roles for SAMdependent methylation reactions and polyamine metabolismin TSC neuropathology. Importantly, both pathways are amenable to nutritional or pharmacologic therapy.

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