Influence of mitochondrial enzyme deficiency on adult neurogenesis in mouse models of neurodegenerative diseases.

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA.
Neuroscience (Impact Factor: 3.12). 07/2008; 153(4):986-96. DOI: 10.1016/j.neuroscience.2008.02.071
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Postmortem neuropathological studies of autism consistently reveal distinctive types of malformations, including cortical dysplasias, heterotopias, and various neuronomorphometric abnormalities. In keeping with these observations, we review here that 88% of high-risk genes for autism influence neural induction and early maturation of the neuroblast. In addition, 80% of these same genes influence later stages of differentiation, including neurite and synapse development, suggesting that these gene products exhibit long-lasting developmental effects on cell development as well as elements of redundancy in processes of neural proliferation, growth, and maturation. We also address the putative genetic overlap of autism with conditions like epilepsy and schizophrenia, with implications to shared and divergent etiologies. This review imports the necessity of a frameshift in our understanding of the neurodevelopmental basis of autism to include all stages of neuronal maturation, ranging from neural induction to synaptogenesis.
    Frontiers in Cellular Neuroscience 11/2014; 8:397. · 4.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abnormal TAR DNA-binding protein 43 (TDP-43) inclusion bodies can be detected in the degenerative neurons of amyotrophic lateral sclerosis. In this study, we induced chronic oxidative stress injury by applying malonate to cultured mouse cortical motor neurons. In the later stages of the malonate insult, TDP-43 expression reduced in the nuclei and transferred to the cytoplasm. This was accompanied by neuronal death, mimicking the pathological changes in TDP-43 that are seen in patients with amyotrophic lateral sclerosis. Interestingly, in the early stages of the response to malonate treatment, nuclear TDP-43 expression increased, and neurons remained relatively intact, without inclusion bodies or fragmentation. Therefore, we hypothesized that the increase of nuclear TDP-43 expression might be a pro-survival factor against oxidative stress injury. This hypothesis was confirmed by an in vitro transgenic experiment, in which overexpression of wild type mouse TDP-43 in cultured cortical motor neurons significantly reduced malonate-induced neuronal death. Our findings suggest that the loss of function of TDP-43 is an important cause of neuronal degeneration, and upregulation of nuclear TDP-43 expression might be neuroprotective in amyotrophic lateral sclerosis.
    Neural Regeneration Research 12/2013; 8(35):3284-95. · 0.14 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Researchers who have uncovered the presence of stem cells in an adult's central nervous system have not only challenged the dogma that new neurons cannot be generated during adulthood, but also shed light on the etiology and disease mechanisms underlying many neurological and psychiatric disorders. Brain trauma, neurodegenerative diseases, and psychiatric disorders pose enormous burdens at both personal and societal levels. Although medications for these disorders are widely used, the treatment mechanisms underlying the illnesses remain largely elusive. In the past decade, an increasing amount of evidence indicate that adult neurogenesis (i.e. generating new CNS neurons during adulthood) may be involved in the pathology of different CNS disorders, and thus neurogenesis may be a potential target area for treatments. Although the new neurons were shown to be a major player in mediating treatment efficacy of neurological and psychotropic drugs on cognitive functions, it is still debatable if the altered production of new neurons can cause the disorders. This review hence seeks to discuss pre and current clinical studies that demonstrate the functional impact adult neurogenesis have on neurological and psychiatric illnesses while examining the related underlying disease mechanisms.
    Progress in Neurobiology 01/2013; · 9.04 Impact Factor

Full-text (3 Sources)

Available from
May 16, 2014