Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase.
Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung-/- embryonic fibroblasts, and conferred death of cultured Ung-/- hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung-/- but not Ung+/+ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in Ung-/- mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency.
Kronenberg
Golo
G
Klinik und Poliklinik für Neurologie, Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Campus Mitte, D-10117 Berlin, Germany.
Harms
Christoph
C
Sobol
Robert W
RW
Cardozo-Pelaez
Fernando
F
Linhart
Heinz
H
Winter
Benjamin
B
Balkaya
Mustafa
M
Gertz
Karen
K
Gay
Shanna B
SB
Cox
David
D
Eckart
Sarah
S
Ahmadi
Michael
M
Juckel
Georg
G
Kempermann
Gerd
G
Hellweg
Rainer
R
Sohr
Reinhard
R
Hörtnagl
Heide
H
Wilson
Samuel H
SH
Jaenisch
Rudolf
R
Endres
Matthias
M
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001927:Brain Diseases / Q000209:etiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003856:Deoxyuracil Nucleotides / Q000378:metabolism; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000502:physiology; D005494:Folic Acid Deficiency / Q000150:complications* / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006710:Homocysteine / Q000097:blood; D018782:Maze Learning / Q000502:physiology; D008715:Methionine / Q000097:blood; D051379:Mice; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism; D013550:Swimming; D051981:Uracil-DNA Glycosidase / Q000172:deficiency*
D019208:Brain-Derived Neurotrophic Factor; D003856:Deoxyuracil Nucleotides; D018377:Neurotransmitter Agents; D006710:Homocysteine; C007267:2'-deoxyuridylic acid; D008715:Methionine; D051981:Uracil-DNA Glycosidase; D005978:Glutathione