Mitochondrial damage modulates alternative splicing in neuronal cells

Implications for neurodegeneration

Alessia Maracchioni, Antonio Totaro, Daniela F. Angelini, Alessandra Di Penta, Giorgio Bernardi, Maria Teresa Carrì, Tilmann Achsel

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Mitochondrial damage is linked to many neurodegenerative conditions, such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. These diseases are associated with changes in the splicing pattern of individual mRNAs. Here, we tested the hypothesis that mitochondrial damage modulates alternative splicing, not only of a few mRNAs, but in a general manner. We incubated cultured human neuroblastoma cells with the chemical agent paraquat (a neurotoxin that interferes with mitochondrial function, causing energy deficit and oxidative stress) and analysed the splicing pattern of 13 genes by RT-PCR. For all mRNAs that are alternatively spliced, we observed a dose- and time-dependent increase of the smaller isoforms. In contrast, splicing of all constitutive splicing exons that we monitored did not change. Using other drugs, we show that the modulation of alternative splicing correlates with ATP depletion, not with oxidative stress. Such drastic changes in alternative splicing are not observed in cell lines of non-neuronal origin, suggesting a selective susceptibility of neuronal cells to modulation of splicing. As a significant percentage of all mammalian mRNAs undergo alternative splicing, we predict that mitochondrial failure will unbalance a vast number of isoform equilibriums, which would give an important contribution to neurodegeneration.

Original languageEnglish
Pages (from-to)142-153
Number of pages12
JournalJournal of Neurochemistry
Volume100
Issue number1
DOIs
Publication statusPublished - Jan 2007

Fingerprint

Alternative Splicing
Messenger RNA
Oxidative stress
Protein Isoforms
Oxidative Stress
Modulation
Paraquat
Neurotoxins
Amyotrophic Lateral Sclerosis
Neuroblastoma
Parkinson Disease
Exons
Alzheimer Disease
Genes
Adenosine Triphosphate
Cells
Cell Line
Polymerase Chain Reaction
Pharmaceutical Preparations

Keywords

  • Alternative splicing
  • Apoptosis protease-activating factor 1
  • Neurodegeneration
  • Survival of motor neurons

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Mitochondrial damage modulates alternative splicing in neuronal cells : Implications for neurodegeneration. / Maracchioni, Alessia; Totaro, Antonio; Angelini, Daniela F.; Di Penta, Alessandra; Bernardi, Giorgio; Carrì, Maria Teresa; Achsel, Tilmann.

In: Journal of Neurochemistry, Vol. 100, No. 1, 01.2007, p. 142-153.

Research output: Contribution to journalArticle

Maracchioni, Alessia ; Totaro, Antonio ; Angelini, Daniela F. ; Di Penta, Alessandra ; Bernardi, Giorgio ; Carrì, Maria Teresa ; Achsel, Tilmann. / Mitochondrial damage modulates alternative splicing in neuronal cells : Implications for neurodegeneration. In: Journal of Neurochemistry. 2007 ; Vol. 100, No. 1. pp. 142-153.
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