Deletion of 2-aminoadipic semialdehyde synthase limits metabolite accumulation in cell and mouse models for glutaric aciduria type 1.
2-Aminoadipic Acid
/ analogs & derivatives
Amino Acid Metabolism, Inborn Errors
/ genetics
Animals
Brain
/ metabolism
Brain Diseases, Metabolic
/ genetics
CRISPR-Cas Systems
Disease Models, Animal
Female
Glutarates
/ metabolism
Glutaryl-CoA Dehydrogenase
/ deficiency
HEK293 Cells
Humans
Liver
/ metabolism
Male
Mice
Mice, Knockout
animal model
glutaric acid
glutaric aciduria
lysine
substrate reduction therapy
Journal
Journal of inherited metabolic disease
ISSN: 1573-2665
Titre abrégé: J Inherit Metab Dis
Pays: United States
ID NLM: 7910918
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
27
04
2020
revised:
04
06
2020
accepted:
17
06
2020
pubmed:
23
6
2020
medline:
8
10
2021
entrez:
23
6
2020
Statut:
ppublish
Résumé
Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by acute encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. We investigated the efficacy of substrate reduction through inhibition of 2-aminoadipic semialdehyde synthase (AASS), an enzyme upstream of the defective glutaryl-CoA dehydrogenase (GCDH), in a cell line and mouse model of GA1. We show that loss of AASS function in GCDH-deficient HEK-293 cells leads to an approximately fivefold reduction in the established GA1 clinical biomarker glutarylcarnitine. In the GA1 mouse model, deletion of Aass leads to a 4.3-, 3.8-, and 3.2-fold decrease in the glutaric acid levels in urine, brain, and liver, respectively. Parallel decreases were observed in urine and brain 3-hydroxyglutaric acid levels, and plasma, urine, and brain glutarylcarnitine levels. These in vivo data demonstrate that the saccharopine pathway is the main source of glutaric acid production in the brain and periphery of a mouse model for GA1, and support the notion that pharmacological inhibition of AASS may represent an attractive strategy to treat GA1.
Substances chimiques
Glutarates
0
2-Aminoadipic Acid
1K7B1OED4N
allysine
425I4Y24YZ
Glutaryl-CoA Dehydrogenase
EC 1.3.8.6
glutaric acid
H849F7N00B
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1154-1164Informations de copyright
© 2020 SSIEM.
Références
Mills PB, Struys E, Jakobs C, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. NatMed. 2006;12(3):307-309.
van Karnebeek CD, Tiebout SA, Niermeijer J, et al. Pyridoxine-dependent epilepsy: an expanding clinical spectrum. Pediatr Neurol. 2016;59:6-12.
Harting I, Neumaier-Probst E, Seitz A, et al. Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. Brain. 2009;132(Pt 7):1764-1782.
Greenberg CR, Reimer D, Singal R, et al. A G-to-T transversion at the +5 position of intron 1 in the glutaryl CoA dehydrogenase gene is associated with the Island Lake variant of glutaric acidemia type I. Hum Mol Genet. 1995;4(3):493-495.
Goodman SI, Stein DE, Schlesinger S, et al. Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): review and report of thirty novel mutations. Hum Mutat. 1998;12(3):141-144.
Boy N, Garbade SF, Heringer J, Seitz A, Kölker S, Harting I. Patterns, evolution, and severity of striatal injury in insidious- versus acute-onset glutaric aciduria type 1. J Inherit Metab Dis. 2019;42(1):117-127.
Funk CB, Prasad AN, Frosk P, et al. Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort. Brain. 2005;128(Pt 4):711-722.
Boy N, Muhlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101.
Dancis J, Hutzler J, Ampola MG, et al. The prognosis of hyperlysinemia: an interim report. Am J Hum Genet. 1983;35(3):438-442.
Goodman SI, Duran M. In: Blau N, Duran M, Gibson KM, Dionisi-Vici C, eds. Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Berlin Heidelberg: Springer Verlag; 2014:691-705.
Houten SM, te Brinke H, Denis S, et al. Genetic basis of hyperlysinemia. Orphanet J Rare Dis. 2013;8:57.
Sacksteder KA, Biery BJ, Morrell JC, et al. Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia. Am J Hum Genet. 2000;66(6):1736-1743.
Hagen J, te Brinke H, Wanders RJ, et al. Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria. J Inherit Metab Dis. 2015;38(5):873-879.
Danhauser K, Sauer SW, Haack TB, et al. DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria. Am J Hum Genet. 2012;91(6):1082-1087.
Pena IA, MacKenzie A, van Karnebeek CDM. Current knowledge for pyridoxine-dependent epilepsy: a 2016 update. Exp Rev Endocrinol Metabol. 2017;12(1):5-20.
Pena IA, Marques LA, Laranjeira AB, et al. Mouse lysine catabolism to aminoadipate occurs primarily through the saccharopine pathway; implications for pyridoxine dependent epilepsy (PDE). Biochim Biophys Acta. 2017;1863(1):121-128.
Biagosch C, Ediga RD, Hensler SV, et al. Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism. Biochim Biophys Acta. 2017;1863(9):2220-2228.
Leandro J, Dodatko T, Aten J, et al. DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo. Hum Mol Genet. 2020;29(7):1168-1179.
Crowther LM, Mathis D, Poms M, Plecko B. New insights into human lysine degradation pathways with relevance to pyridoxine dependent epilepsy due to antiquitin deficiency. J Inherit Metab Dis. 2019;42(4):620-628.
Cederbaum SD, Shaw KN, Dancis J, Hutzler J, Blaskovics JC. Hyperlysinemia with saccharopinuria due to combined lysine-ketoglutarate reductase and saccharopine dehydrogenase deficiencies presenting as cystinuria. JPediatr. 1979;95(2):234-238.
Tondo M, Calpena E, Arriola G, et al. Clinical, biochemical, molecular and therapeutic aspects of 2 new cases of 2-aminoadipic semialdehyde synthase deficiency. Mol Genet Metab. 2013;110(3):231-236.
Zhou J, Wang X, Wang M, et al. The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis. J Cell Biol. 2019;218(2):580-597.
Leandro J, Houten SM. Saccharopine, a lysine degradation intermediate, is a mitochondrial toxin. J Cell Biol. 2019;218(2):391-392.
Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8(11):2281-2308.
Violante S, Achetib N, van Roermund CWT, et al. Peroxisomes can oxidize medium- and long-chain fatty acids through a pathway involving ABCD3 and HSD17B4. FASEB J. 2019;33(3):4355-4364.
Koeller DM, Woontner M, Crnic LS, et al. Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I. Hum Mol Genet. 2002;11(4):347-357.
Miller MJ, Kennedy AD, Eckhart AD, et al. Untargeted metabolomic analysis for the clinical screening of inborn errors of metabolism. J Inherit Metab Dis. 2015;38(6):1029-1039.
Evans AM, Bridgewater BR, Miller LAD, et al. High resolution mass spectrometry improves data quantity and quality as compared to unit mass resolution mass spectrometry in high-throughput profiling metabolomics. Metabolomics. 2014;4(2):132
Ozalp I, Hasanoglu A, Tuncbilek E, Yalaz K. Hyperlysinemia without clinical findings. Acta Paediatr Scand. 1981;70(6):951-953.
Sauer SW, Opp S, Hoffmann GF, Koeller DM, Okun JG, Kölker S. Therapeutic modulation of cerebral L-lysine metabolism in a mouse model for glutaric aciduria type I. Brain. 2011;134(Pt 1):157-170.
Sauer SW, Okun JG, Fricker G, et al. Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem. 2006;97(3):899-910.
Zinnanti WJ, Lazovic J, Wolpert EB, et al. A diet-induced mouse model for glutaric aciduria type I. Brain. 2006;129(Pt 4):899-910.
Mack M, Schniegler-Mattox U, Peters V, et al. Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism. FEBS J. 2006;273(9):2012-2022.
Peters V, Morath M, Mack M, et al. Formation of 3-hydroxyglutaric acid in glutaric aciduria type I: in vitro participation of medium chain acyl-CoA dehydrogenase. JIMD Rep. 2019;47(1):30-34.
Zinnanti WJ, Lazovic J, Housman C, et al. Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I. J Clin Invest. 2007;117(11):3258-3270.
Sauer SW, Opp S, Komatsuzaki S, et al. Multifactorial modulation of susceptibility to l-lysine in an animal model of glutaric aciduria type I. Biochim Biophys Acta. 2015;1852(5):768-777.
Yamaguchi S, Orii T, Yasuda K, Kohno Y. A case of glutaric aciduria type I with unique abnormalities in the cerebral CT findings. Tohoku J Exp Med. 1987;151(3):293-299.
Brandt NJ, Gregersen N, Christensen E, Gron IH, Rasmussen K. Treatment of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria). Experience with diet, riboflavin, and GABA analogue. J Pediatr. 1979;94(4):669-673.
Bennett MJ, Marlow N, Pollitt RJ, Wales JK. Glutaric aciduria type 1: biochemical investigations and postmortem findings. Eur J Pediatr. 1986;145(5):403-405.
Whelan DT, Hill R, Ryan ED, Spate ML. Glutaric acidemia: investigation of a patient and his family. Pediatrics. 1979;63(1):88-93.
Goodman SI, Markey SP, Moe PG, Miles BS, Teng CC. Glutaric aciduria: a "new" disorder of amino acid metabolism. Biochem Med. 1975;12(1):12-21.
Hoffmann GF, Trefz FK, Barth PG, et al. Glutaryl-coenzyme A dehydrogenase deficiency: a distinct encephalopathy. Pediatrics. 1991;88(6):1194-1203.
Hoffmann GF, Athanassopoulos S, Burlina AB, et al. Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropediatrics. 1996;27(3):115-123.
GTEx Consortium. Human genomics. The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348(6235):648-660.
Hallen A, Jamie JF, Cooper AJ. Lysine metabolism in mammalian brain: an update on the importance of recent discoveries. Amino Acids. 2013;45(6):1249-1272.
Woody NC, Pupene MB. Excretion of pipecolic acid by infants and by patients with hyperlysinemia. PediatrRes. 1970;4(1):89-95.
Posset R, Opp S, Struys EA, et al. Understanding cerebral L-lysine metabolism: the role of L-pipecolate metabolism in Gcdh-deficient mice as a model for glutaric aciduria type I. J Inherit Metab Dis. 2015;38(2):265-272.
Frimpter GW. Cystathioninuria in a patient with cystinuria. Am J Med. 1969;46(5):832-836.
Strickler JC, Frimpter GW. Renal excretion of cystathionine in dogs. Am J Physiol. 1969;217(4):1199-1204.
Hoppe A, Denneberg T, Jeppsson JO, Kagedal B. Urinary excretion of amino acids in normal and cystinuric dogs. Br Vet J. 1993;149(3):253-268.