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Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase

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Item Type:Review
Title:Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase
Creators Name:Kronenberg, G. and Harms, C. and Sobol, R.W. and Cardozo-Pelaez, F. and Linhart, H. and Winter, B. and Balkaya, M. and Gertz, K. and Gay, S.B. and Cox, D. and Eckart, S. and Ahmadi, M. and Juckel, G. and Kempermann, G. and Hellweg, R. and Sohr, R. and Hoertnagl, H. and Wilson, S.H. and Jaenisch, R. and Endres, M.
Abstract: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.
Keywords:Neurodegeneration, Memory Impairment, Despair, Folate Deficiency, Base Excision Repair, Neurogenesis, Animals, Mice
Source:Journal of Neuroscience
ISSN:0270-6474
Publisher:Society for Neuroscience (U.S.A.)
Volume:28
Number:28
Page Range:7219-7230
Date:9 July 2008
Additional Information:Copyright (c) 2008 by The Society for Neuroscience
Official Publication:https://doi.org/10.1523/JNEUROSCI.0940-08.2008
PubMed:View item in PubMed

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