AMPD2 Regulates GTP Synthesis and Is Mutated in a Potentially Treatable Neurodegenerative Brainstem Disorder

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dc.authoridVaux, Keith/0000-0001-8738-5940|Zaki, Maha/0000-0001-7840-0002|Cantagrel, Vincent/0000-0002-5180-4848|Spencer, Emily/0000-0003-2650-4357|Lipton, Stuart/0000-0002-3490-1259;
dc.contributor.authorAkizu, Naiara
dc.contributor.authorCantagrel, Vincent
dc.contributor.authorSchroth, Jana
dc.contributor.authorCai, Na
dc.contributor.authorVaux, Keith
dc.contributor.authorMcCloskey, Douglas
dc.contributor.authorNaviaux, Robert K.
dc.date.accessioned2025-10-24T18:08:59Z
dc.date.available2025-10-24T18:08:59Z
dc.date.issued2013
dc.departmentMalatya Turgut Özal Üniversitesi
dc.description.abstractPurine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neuro degenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease.
dc.description.sponsorshipCalifornia Institute for Regenerative Medicine; UCSD Christini Fund; Jane Botsford Johnson Foundation; NIH [P01HD070494, R01NS048453, P30NS047101]; Broad Institute grant [U54HG003067]; Simons Foundation Autism Research Initiative
dc.description.sponsorshipWe thank the families for their participation. We also thank B. Daignan-Fornier and B. Pinson for the tet-AMD1 plasmid and helpful advice, A. Hopper and T. Yoshihisa for the sen2-41 yeast strain, E. Masliah and S. Michael for human brain specimens, and S.J. Elledge for pINDUCER20 plasmid. We thank T. Friedman, W. Nyhan, B. Barshop, R. Evans, J. Cheng, and D. Wolf for helpful discussions. N.A. was supported by the California Institute for Regenerative Medicine. R.K.N. was supported by grants from the UCSD Christini Fund and the Jane Botsford Johnson Foundation. This work was supported by the NIH (P01HD070494, R01NS048453, and P30NS047101 for imaging support), Broad Institute grant U54HG003067 (to Eric Lander), the Center for Inherited Disease Research for genotyping, and the Simons Foundation Autism Research Initiative.
dc.identifier.doi10.1016/j.cell.2013.07.005
dc.identifier.endpage517
dc.identifier.issn0092-8674
dc.identifier.issn1097-4172
dc.identifier.issue3
dc.identifier.pmid23911318
dc.identifier.scopus2-s2.0-84881193117
dc.identifier.scopusqualityQ1
dc.identifier.startpage505
dc.identifier.urihttps://doi.org/10.1016/j.cell.2013.07.005
dc.identifier.urihttps://hdl.handle.net/20.500.12899/3394
dc.identifier.volume154
dc.identifier.wosWOS:000322629900006
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherCell Press
dc.relation.ispartofCell
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_20251023
dc.subjectProtein-Synthesis; Pontocerebellar Hypoplasia; Nucleotide Depletion; Yeast; Deficiency; Deaminase; Toxicity; Purine; Gene; Phosphoribosyltransferase
dc.titleAMPD2 Regulates GTP Synthesis and Is Mutated in a Potentially Treatable Neurodegenerative Brainstem Disorder
dc.title.alternativeXAMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder
dc.typeArticle

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