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The Journal of Neuroscience, July 9, 2008, 28(28):7219-7230; doi:10.1523/JNEUROSCI.0940-08.2008

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Neurobiology of Disease
Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase

Golo Kronenberg,^1,2,4 * Christoph Harms,^1 * Robert W. Sobol,^5,6,7 Fernando Cardozo-Pelaez,⁸ Heinz Linhart,⁹ Benjamin Winter,¹ Mustafa Balkaya,¹ Karen Gertz,¹ Shanna B. Gay,⁶ David Cox,⁸ Sarah Eckart,⁴ Michael Ahmadi,¹ Georg Juckel,¹⁰ Gerd Kempermann,^1,11 Rainer Hellweg,⁴ Reinhard Sohr,³ Heide Hörtnagl,³ Samuel H. Wilson,⁷ Rudolf Jaenisch,⁹ and Matthias Endres^1,2

¹Klinik und Poliklinik für Neurologie, ²Center for Stroke Research Berlin, and ³Institut für Pharmakologie und Toxikologie, Charité-Universitätsmedizin Berlin, Campus Mitte, D-10117 Berlin, Germany, ⁴Klinik und Hochschulambulanz für Psychiatrie und Psychotherapie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 14050 Berlin, Germany, ⁵Department of Pharmacology, University of Pittsburgh School of Medicine and ⁶University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania 15213-1863, ⁷Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 277096, ⁸Department of Biomedical and Pharmaceutical Sciences, Center for Environmental Health Sciences, University of Montana, Missoula, Montana 59812, ⁹Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, ¹⁰Westfälisches Zentrum, Ruhr-Universität Bochum, D-44791 Bochum, Germany, and ¹¹Max Delbrück Center for Molecular Medicine, D-13125 Berlin-Buch, Germany

Correspondence should be addressed to Dr. Matthias Endres, Klinik und Poliklinik für Neurologie, Charité-Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, D-10117 Berlin, Germany. Email: matthias.endres{at}charite.de

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.

Key words: neurodegeneration; memory impairment; despair; folate deficiency; base excision repair; neurogenesis

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Received April 19, 2007; accepted March 31, 2008.

Correspondence should be addressed to Dr. Matthias Endres, Klinik und Poliklinik für Neurologie, Charité-Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, D-10117 Berlin, Germany. Email: matthias.endres{at}charite.de

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