AMPD2 Regulates GTP Synthesis and Is Mutated in a Potentially Treatable Neurodegenerative Brainstem Disorder
Küçük Resim Yok
Tarih
2013
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Cell Press
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
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 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.
Açıklama
Anahtar Kelimeler
Protein-Synthesis; Pontocerebellar Hypoplasia; Nucleotide Depletion; Yeast; Deficiency; Deaminase; Toxicity; Purine; Gene; Phosphoribosyltransferase
Kaynak
Cell
WoS Q Değeri
Q1
Scopus Q Değeri
Q1
Cilt
154
Sayı
3
