Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice.
Thymidine phosphorylase (TP) regulates intracellular and plasma thymidine levels. TP deficiency is hypothesized to (i) increase levels of thymidine in plasma, (ii) lead to mitochondrial DNA alterations, and (iii) cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In order to elucidate the physiological roles of TP, we generated mice deficient in the TP gene. Although TP activity in the liver was inhibited in these mice, it was fully maintained in the small intestine. Murine uridine phosphorylase (UP), unlike human UP, cleaves thymidine, as well as uridine. We therefore generated TP-UP double-knockout (TP(-/-) UP(-/-)) mice. TP activities were inhibited in TP(-/-) UP(-/-) mice, and the level of thymidine in the plasma of TP(-/-) UP(-/-) mice was higher than for TP(-/-) mice. Unexpectedly, we could not observe alterations of mitochondrial DNA or pathological changes in the muscles of the TP(-/-) UP(-/-) mice, even when these mice were fed thymidine for 7 months. However, we did find hyperintense lesions on magnetic resonance T(2) maps in the brain and axonal edema by electron microscopic study of the brain in TP(-/-) UP(-/-) mice. These findings suggested that the inhibition of TP activity caused the elevation of pyrimidine levels in plasma and consequent axonal swelling in the brains of mice. Since lesions in the brain do not appear to be due to mitochondrial alterations and pathological changes in the muscle were not found, this model will provide further insights into the causes of MNGIE.
Haraguchi
Misako
M
Department of Cancer Chemotherapy, Institute for Cancer Research, Third Department of Internal Medicin, Kagoshima University, 8-35-1 Sakura-gaoka, Kagoshima 890-8520, Japan.
Tsujimoto
Hiroaki
H
Fukushima
Masakazu
M
Higuchi
Itsuro
I
Kuribayashi
Hideto
H
Utsumi
Hideo
H
Nakayama
Atsuo
A
Hashizume
Yoshio
Y
Hirato
Junko
J
Yoshida
Hiroki
H
Hara
Hiromitsu
H
Hamano
Shinjiro
S
Kawaguchi
Hiroaki
H
Furukawa
Tatsuhiko
T
Miyazono
Kohei
K
Ishikawa
Fuyuki
F
Toyoshima
Hideo
H
Kaname
Tadashi
T
Komatsu
Masaharu
M
Chen
Zhe-Sheng
ZS
Gotanda
Takenari
T
Tachiwada
Tokushi
T
Sumizawa
Tomoyuki
T
Miyadera
Kazutaka
K
Osame
Mitsuhiro
M
Yoshida
Hiroki
H
Noda
Tetsuo
T
Yamada
Yuji
Y
Akiyama
Shin-ichi
S
D000818:Animals; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D018390:Gene Targeting; D006801:Humans; D007421:Intestine, Small / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D013939:Thymidine Phosphorylase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014543:Uridine Phosphorylase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D014543:Uridine Phosphorylase; D013939:Thymidine Phosphorylase