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

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 α-difluoromethylornithine, to reduce putrescine synthesis dose-dependently reduced hippocampal astrogliosis. These data establish roles for SAM-dependent methylation reactions and polyamine metabolism in TSC neuropathology. Importantly, both pathways are amenable to nutritional or pharmacologic therapy.

Severe Spinal Cord Injury in Rats Induces Chronic Changes in the Spinal Cord and Cerebral Cortex Metabolism, Adjusted by Thiamine That Improves Locomotor Performance

“…Lysine also generates polyamines that are part of the stress response systems in living organisms ( Olin-Sandoval et al, 2019 ; Sakamoto et al, 2020 ; Wu et al, 2020 ). In this regard, also our observation of the strong positive correlation between BBB and cystathionine deserves attention, because reduced cystathionine is a marker of changed transmethylation and polyamine synthesis, associated with the mTORC1-controlled astrogliosis and pathological anabolism ( McKenna et al, 2018 ). In our model of SCI, such events may well develop due to a long-standing failure to properly re-establish the functions of the damaged spinal cord.…”

Human pluripotent stem cell modeling of tuberous sclerosis complex reveals lineage-specific therapeutic vulnerabilities

“…Our data reconcile these previous observations by revealing that TSC2 -/neural lineage cells, but not NCCs or hPSCs, uniquely develop elevated endosomal signaling mechanisms, and that these are established during early stages of lineage specification. Mitochondrial and metabolic defects, as well as proteasome dysfunction, have also been identified as potential therapeutic targets for both neurological and mesenchymal TSC (Abdelwahab et al, 2019;Ebrahimi-Fakhari et al, 2016;McKenna III et al, 2018;Parkhitko et al, 2014;Siroky et al, 2012;Van Scheppingen et al, 2016). These previous studies did not, however, permit analysis of the development of these phenotypes during lineage specification;…”

Polyamine Homeostasis in Snyder-Robinson Syndrome

“…Similarly altered polyamine metabolism was also recently described in a mouse model of tuberous sclerosis complex (TSC), a neurodevelopmental disorder associated with mechanistic Target of Rapamycin Complex 1 (mTORC1) dysregulation. TSC also shares clinical manifestations with SRS, including intellectual disability and epileptic seizures, and inhibition of ODC reduced astrogliosis, an indicator of TSC neuropathology [40]. The common neurological phenotypes resulting from mutations in SMS , ODC1 , and TSC and their association with dysregulated polyamine metabolism suggest that the knowledge obtained from the current studies might serve to benefit a patient population beyond those with Snyder-Robinson Syndrome.…”