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Mitochondrial Oxidative Phosphorylation Transcriptome Alterations in Human Amyotrophic Lateral Sclerosis Spinal Cord and Blood

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Abstract

Origins of onset and progression of motor neurodegeneration in amyotrophic lateral sclerosis (ALS) are not clearly known, but may include impairment of mitochondrial bioenergetics. We used quantitative PCR approaches to analyze the mitochondrial oxidative phosphorylation (OXPHOS) transcriptomes of spinal cord tissue and peripheral blood mononuclear cells (PBMC) from persons with sporadic ALS compared with those without neurological disease. Expression measurements of 88 different nuclear (n) and mitochondrial (mt) DNA-encoded OXPHOS genes showed mtDNA-encoded respiratory gene expression was significantly decreased in ALS spinal cord by 78–84 % (ANOVA p < 0.002). We observed the same phenomenon in freshly isolated PBMC from ALS patients (reduced 24–35 %, ANOVA p < 0.001) and reproduced it in a human neural stem cell model treated with 2′,3′-dideoxycytidine (ddC) (reduced 52–78 %, ANOVA p < 0.001). nDNA-encoded OXPHOS genes showed heterogeneously and mostly decreased expression in ALS spinal cord tissue. In contrast, ALS PBMC and ddC-treated stem cells showed no significant change in expression of nDNA OXPHOS genes compared with controls. Genes related to mitochondrial biogenesis (PGC-1α, TFAM, ERRα, NRF1, NRF2 and POLG) were queried with inconclusive results. Here, we demonstrate there is a systemic decrease in mtDNA gene expression in ALS central and peripheral tissues that support pursuit of bioenergetic-enhancing therapies. We also identified a combined nDNA and mtDNA gene set (n = 26), downregulated in spinal cord tissue that may be useful as a biomarker in the development of cell-based ALS models.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

CTL:

Control

ddC:

2′,3′-Dideoxycytidine

fbRNA:

Commercially available fetal brain RNA

hSC:

Human spinal cord

mtDNA:

Mitochondrial DNA

nDNA:

Nuclear DNA

NSC:

Neural stem cells

OXPHOS:

Oxidative phosphorylation

PBMC:

Peripheral blood mononuclear cells

qPCR:

Quantitative PCR

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Acknowledgments

This research was supported by the Parkinson’s and Movement Disorders Center at Virginia Commonwealth University through the Medical College of Virginia Foundation.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

Anonymous, frozen cervical hSC specimens (n = 16) were acquired from the National Disease Research Interchange, Philadelphia, PA http://www.ndri-resource.org. Peripheral blood (n = 20) from nine ALS and eleven non-ALS healthy control patients was collected in accordance with a VCU IRB-approved protocol at the Parkinson’s and Movement Disorder’s Center at our institution.

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Authors and Affiliations

  1. Parkinson’s and Movement Disorders Center, Virginia Commonwealth University, P.O. Box 980312, Richmond, VA, 23298, USA

    Amy C. Ladd, Paula M. Keeney, Maria M. Govind & James P. Bennett Jr.

  2. Department of Neurology, Virginia Commonwealth University, P.O. Box 980312, Richmond, VA, 23298, USA

    James P. Bennett Jr.

  3. Department of Psychiatry, Virginia Commonwealth University, P.O. Box 980312, Richmond, VA, 23298, USA

    James P. Bennett Jr.

  4. Department of Physiology and Biophysics, Virginia Commonwealth University, P.O. Box 980312, Richmond, VA, 23298, USA

    James P. Bennett Jr.

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  1. Amy C. Ladd
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  2. Paula M. Keeney
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  3. Maria M. Govind
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  4. James P. Bennett Jr.
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Correspondence to Amy C. Ladd.

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Ladd, A.C., Keeney, P.M., Govind, M.M. et al. Mitochondrial Oxidative Phosphorylation Transcriptome Alterations in Human Amyotrophic Lateral Sclerosis Spinal Cord and Blood. Neuromol Med 16, 714–726 (2014). https://doi.org/10.1007/s12017-014-8321-y

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