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Ladd 2017 Brain Res

From Bioblast
Publications in the MiPMap
Ladd AC, Brohawn DG, Thomas RR, Keeney PM, Berr SS, Khan SM, Portell FR, Shakenov MZ, Antkowiak PF, Kundu B, Tustison N, Bennett JP (2017) RNA-seq analyses reveal that cervical spinal cords and anterior motor neurons from amyotrophic lateral sclerosis subjects show reduced expression of mitochondrial DNA-encoded respiratory genes, and rhTFAM may correct this respiratory deficiency. Brain Res 1667:74-83.

» PMID: 28511992

Ladd AC, Brohawn DG, Thomas RR, Keeney PM, Berr SS, Khan SM, Portell FR, Shakenov MZ, Antkowiak PF, Kundu B, Tustison N, Bennett JP (2017) Brain Res

Abstract: Amyotrophic lateral sclerosis (ALS) is a generally fatal neurodegenerative disease of adults that produces weakness and atrophy due to dysfunction and death of upper and lower motor neurons. We used RNA-sequencing (RNA-seq) to analyze expression of all mitochondrial DNA (mtDNA)-encoded respiratory genes in ALS and CTL human cervical spinal cords (hCSC) and isolated motor neurons. We analyzed with RNA-seq mtDNA gene expression in human neural stem cells (hNSC) exposed to recombinant human mitochondrial transcription factor A (rhTFAM), visualized in 3-dimensions clustered gene networks activated by rhTFAM, quantitated their interactions with other genes and determined their gene ontology (GO) families. RNA-seq and quantitative PCR (qPCR) analyses showed reduced mitochondrial gene expression in ALS hCSC and ALS motor neurons isolated by laser capture microdissection (LCM), and revealed that hNSC and CTL human cervical spinal cords were similar. Rats treated with i.v. rhTFAM showed a dose-response increase in brain respiration and an increase in spinal cord mitochondrial gene expression. Treatment of hNSC with rhTFAM increased expression of mtDNA-encoded respiratory genes and produced one major and several minor clusters of gene interactions. Gene ontology (GO) analysis of rhTFAM-stimulated gene clusters revealed enrichment in GO families involved in RNA and mRNA metabolism, suggesting mitochondrial-nuclear signaling. In postmortem ALS hCSC and LCM-isolated motor neurons we found reduced expression of mtDNA respiratory genes. In hNSC's rhTFAM increased mtDNA gene expression and stimulated mRNA metabolism by unclear mechanisms. rhTFAM may be useful in improving bioenergetic function in ALS.

Copyright © 2017 Elsevier B.V. All rights reserved. Keywords: ALS, Genomics, Mitochondria, RNA expression, TFAM Bioblast editor: Kandolf G O2k-Network Lab: US VA Richmond Bennett JP

Labels: MiParea: Respiration, mtDNA;mt-genetics  Pathology: Neurodegenerative 

Organism: Rat  Tissue;cell: Nervous system  Preparation: Homogenate 

Coupling state: LEAK, OXPHOS  Pathway: N, S, CIV  HRR: Oxygraph-2k