A role for voltage-dependent anion channel Vdac1 in polyglutamine-mediated neuronal cell death.
Expansion of trinucleotide repeats in coding and non-coding regions of genes is associated with sixteen neurodegenerative disorders. However, the molecular effects that lead to neurodegeneration have remained elusive. We have explored the role of transcriptional dysregulation by TATA-box binding protein (TBP) containing an expanded polyglutamine stretch in a mouse neuronal cell culture based model. We find that mouse neuronal cells expressing a variant of human TBP harboring an abnormally expanded polyQ tract not only form intranuclear aggregates, but also show transcription dysregulation of the voltage dependent anion channel, Vdac1, increased cytochrome c release from the mitochondria and upregulation of genes involved in localized neuronal translation. On the other hand, unfolded protein response seemed to be unaffected. Consistent with an increased transcriptional effect, we observe an elevated promoter occupancy by TBP in vivo in TATA containing and TATA-less promoters of differentially expressed genes. Our study suggests a link between transcriptional dysfunction and cell death in trinucleotide repeat mediated neuronal dysfunction through voltage dependent anion channel, Vdac1, which has been recently recognized as a critical determinant of cell death.
Ghosh
Tanay
T
Institute of Genomics and Integrative Biology (IGIB), New Delhi, India.
Pandey
Neeraj
N
Maitra
Arindam
A
Brahmachari
Samir K
SK
Pillai
Beena
B
D000818:Animals; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D050995:Voltage-Dependent Anion Channel 1 / Q000502:physiology*
D017931:DNA Primers; D010455:Peptides; C494762:VDAC1 protein, human; C097188:polyglutamine; D050995:Voltage-Dependent Anion Channel 1