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Akizu, Naiara; Cantagrel, Vincent; Schroth, Jana; Cai, Na; Vaux, Keith; McCloskey, Douglas; Naviaux, Robert K.; Van Vleet, Jeremy; Fenstermaker, Ali G.; Silhavy, Jennifer L.; Scheliga, Judith S.; Toyama, Keiko; Morisaki, Hiroko; Sonmez, Fatma M.; Celep, Figen; Oraby, Azza; Zaki, Maha S.; Al-Baradie, Raidah; Faqeih, Eissa A.; Saleh, Mohammed A.M.; Spencer, Emily; Rosti, Rasim Ozgur; Scott, Eric; Nickerson, Elizabeth; Gabriel, Stacey; Morisaki, Takayuki; Holmes, Edward W.; Gleeson, Joseph G.
Cell, 08/2013, Letnik: 154, Številka: 3Journal Article
Purine 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 neurodegenerative 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. Display omitted •Mutations in AMPD2, an essential gene for purine metabolism, lead to PCH9•AMPD2 mutations lead to GTP depletion and impaired protein synthesis•AMPD2 is necessary for neural cell survival upon adenosine-induced stress•Cell death is prevented by bypassing the block in de novo purine synthesis Mutations in the gene AMPD2 cause a purine metabolism disorder marked by early-onset brainstem and cerebellum neurodegeneration. Bypassing the block in de novo purine synthesis prevents neuronal toxicity, suggesting a therapeutic mode for this neurodegenerative disorder.
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