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ABSTRACT: Mitochondrial defects including reduction of a key mitochondrial tricarboxylic acid cycle enzyme alpha-ketoglutarate-dehydrogenase complex (KGDHC) are characteristic of many neurodegenerative diseases. KGDHC consists of alpha-ketoglutarate dehydrogenase, dihydrolipoyl succinyltransferase (E2k), and dihydrolipoamide dehydrogenase (Dld) subunits. We investigated whether Dld or E2k deficiency influences adult brain neurogenesis using immunohistochemistry for the immature neuron markers, doublecortin (Dcx) and polysialic acid-neural cell adhesion molecule, as well as a marker for proliferation, proliferating cell nuclear antigen (PCNA). Both Dld- and E2k-deficient mice showed reduced Dcx-positive neuroblasts in the subgranular zone (SGZ) of the hippocampal dentate gyrus compared with wild-type mice. In the E2k knockout mice, increased immunoreactivity for the lipid peroxidation marker, malondialdehyde occurred in the SGZ. These alterations did not occur in the subventricular zone (SVZ). PCNA staining revealed decreased proliferation in the SGZ of E2k-deficient mice. In a transgenic mouse model of Alzheimer's disease, Dcx-positive cells in the SGZ were also reduced compared with wild type, but Dld deficiency did not exacerbate the reduction. In the malonate lesion model of Huntington's disease, Dld deficiency did not alter the lesion-induced increase and migration of Dcx-positive cells from the SVZ into the ipsilateral striatum. Thus, the KGDHC subunit deficiencies associated with elevated lipid peroxidation selectively reduced the number of neuroblasts and proliferating cells in the hippocampal neurogenic zone. However, these mitochondrial defects neither exacerbated certain pathological conditions, such as amyloid precursor protein (APP) mutation-induced reduction of SGZ neuroblasts, nor inhibited malonate-induced migration of SVZ neuroblasts. Our findings support the view that mitochondrial dysfunction can influence the number of neural progenitor cells in the hippocampus of adult mice.
Neuroscience 07/2008; 153(4):986-96. · 3.38 Impact Factor
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ABSTRACT: Thiamine-dependent enzymes are diminished in multiple neurodegenerative diseases. Thiamine deficiency (TD) reduces the activity of thiamine dependent-enzymes [e.g., the alpha-ketoglutarate dehydrogenase complex (KGDHC)], induces regional selective neurodegeneration and serves as a model of a mild impairment of oxidative metabolism. The current experiments tested whether changes in KGDHC protein subunits (E1k, E2k and E3) or activity or message levels underlie the selective loss of neurons in particular brain regions. Thus, TD-induced changes in these variables in the brain region most vulnerable to TD [the sub-medial thalamic nucleus (SmTN)] were compared to those in a region that is relatively resistant to TD (cortex) at stages of TD when the neuron loss in SmTN is not present, minimal or severe. Impaired motor performance on rotarod was apparent by 8 days of TD (-32%) and was severe by 10 days of TD (-97%). At TD10, the overall KGDHC activity measured by an in situ histochemical staining method declined 52% in SmTN but only 20% in cortex. Reductions in the E2k and E3 mRNA in SmTN occurred as early as TD6 (-28 and -18%, respectively) and were more severe by TD10 (-61 and -66%, respectively). On the other hand, the level of E1k mRNA did not decline in SmTN until TD10 (-48%). In contrast, TD did not alter mRNA levels of the subunits in cortex at late stages. Western blots and immunocytochemistry revealed different aspects of the changes in protein levels. In SmTN, the immunoreactivity of E1k and E3 by Western blotting increased 34 and 40%, respectively, only at TD8. In cortex, the immunoreactivity of the three subunits was not altered. Immunocytochemical staining of brain sections from TD10 mice indicated a reduction in the immunoreactivity of all subunits in SmTN, but not in cortex. These findings demonstrate that the response of the KGDHC activity, mRNA and immunoreactivity of E1k, E2k and E3 to TD is region and time dependent. Loss of KGDHC activity in cortex is likely related to post-translational modification rather than a loss of protein, whereas in SmTN transcriptional and post-translational modifications may account for diminished KGDHC activity. Moreover, the earlier detection in TD induced-changes of the transcripts of KGDHC indicates that transcriptional modification of the two subunits (E2k and E3) of KGDHC may be one of the early events in the cascade leading to selective neuronal death.
Neurochemistry International 07/2007; 50(7-8):921-31. · 2.86 Impact Factor
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ABSTRACT: Brain metabolism and the activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a mitochondrial enzyme, are diminished in brains from patients with Alzheimer's disease (AD). In 109 subjects, the Clinical Dementia Rating (CDR) score was highly correlated with brain KGDHC activity. In AD patients who carried the epsilon 4 allele of the apolipoprotein E gene (ApoE4), the CDR score correlated better with KGDHC activity than with the densities of neuritic plaques or neuritic tangles. In contrast, in patients without ApoE4, the CDR score correlated significantly better with tangles and plaques than with KGDHC activity. The results suggest that mitochondrial/oxidative damage may be more important for the cognitive dysfunction in AD patients who carry ApoE4 than in those who do not.
Annals of Neurology 10/2000; 48(3):297-303. · 11.09 Impact Factor
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ABSTRACT: Thiamine-dependent enzymes are diminished in multiple neurodegenerative diseases. Thiamine deficiency (TD) reduces the activity of thiamine dependent-enzymes [e.g., the α-ketoglutarate dehydrogenase complex (KGDHC)], induces regional selective neurodegeneration and serves as a model of a mild impairment of oxidative metabolism. The current experiments tested whether changes in KGDHC protein subunits (E1k, E2k and E3) or activity or message levels underlie the selective loss of neurons in particular brain regions. Thus, TD-induced changes in these variables in the brain region most vulnerable to TD [the sub-medial thalamic nucleus (SmTN)] were compared to those in a region that is relatively resistant to TD (cortex) at stages of TD when the neuron loss in SmTN is not present, minimal or severe. Impaired motor performance on rotarod was apparent by 8 days of TD (−32%) and was severe by 10 days of TD (−97%). At TD10, the overall KGDHC activity measured by an in situ histochemical staining method declined 52% in SmTN but only 20% in cortex. Reductions in the E2k and E3 mRNA in SmTN occurred as early as TD6 (−28 and −18%, respectively) and were more severe by TD10 (−61 and −66%, respectively). On the other hand, the level of E1k mRNA did not decline in SmTN until TD10 (−48%). In contrast, TD did not alter mRNA levels of the subunits in cortex at late stages. Western blots and immunocytochemistry revealed different aspects of the changes in protein levels. In SmTN, the immunoreactivity of E1k and E3 by Western blotting increased 34 and 40%, respectively, only at TD8. In cortex, the immunoreactivity of the three subunits was not altered. Immunocytochemical staining of brain sections from TD10 mice indicated a reduction in the immunoreactivity of all subunits in SmTN, but not in cortex. These findings demonstrate that the response of the KGDHC activity, mRNA and immunoreactivity of E1k, E2k and E3 to TD is region and time dependent. Loss of KGDHC activity in cortex is likely related to post-translational modification rather than a loss of protein, whereas in SmTN transcriptional and post-translational modifications may account for diminished KGDHC activity. Moreover, the earlier detection in TD induced-changes of the transcripts of KGDHC indicates that transcriptional modification of the two subunits (E2k and E3) of KGDHC may be one of the early events in the cascade leading to selective neuronal death.
Neurochemistry International.
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[show abstract]
[hide abstract]
ABSTRACT: Mitochondrial defects including reduction of a key mitochondrial tricarboxylic acid cycle enzyme α-ketoglutarate–dehydrogenase complex (KGDHC) are characteristic of many neurodegenerative diseases. KGDHC consists of α-ketoglutarate dehydrogenase, dihydrolipoyl succinyltransferase (E2k), and dihydrolipoamide dehydrogenase (Dld) subunits. We investigated whether Dld or E2k deficiency influences adult brain neurogenesis using immunohistochemistry for the immature neuron markers, doublecortin (Dcx) and polysialic acid–neural cell adhesion molecule, as well as a marker for proliferation, proliferating cell nuclear antigen (PCNA). Both Dld- and E2k-deficient mice showed reduced Dcx-positive neuroblasts in the subgranular zone (SGZ) of the hippocampal dentate gyrus compared with wild-type mice. In the E2k knockout mice, increased immunoreactivity for the lipid peroxidation marker, malondialdehyde occurred in the SGZ. These alterations did not occur in the subventricular zone (SVZ). PCNA staining revealed decreased proliferation in the SGZ of E2k-deficient mice. In a transgenic mouse model of Alzheimer's disease, Dcx-positive cells in the SGZ were also reduced compared with wild type, but Dld deficiency did not exacerbate the reduction. In the malonate lesion model of Huntington's disease, Dld deficiency did not alter the lesion-induced increase and migration of Dcx-positive cells from the SVZ into the ipsilateral striatum. Thus, the KGDHC subunit deficiencies associated with elevated lipid peroxidation selectively reduced the number of neuroblasts and proliferating cells in the hippocampal neurogenic zone. However, these mitochondrial defects neither exacerbated certain pathological conditions, such as amyloid precursor protein (APP) mutation-induced reduction of SGZ neuroblasts, nor inhibited malonate-induced migration of SVZ neuroblasts. Our findings support the view that mitochondrial dysfunction can influence the number of neural progenitor cells in the hippocampus of adult mice.
Neuroscience.
