Cytoplasmic inclusions of Htt exon1 containing an expanded polyglutamine tract suppress execution of apoptosis in sympathetic neurons.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Matthew A KingAviva M Tolkovsky

Abstract

Proteins containing extended polyglutamine repeats cause at least nine neurodegenerative disorders, but the mechanisms of disease-related neuronal death remain uncertain. We show that sympathetic neurons containing cytoplasmic inclusions formed by 97 glutamines expressed within human huntingtin exon1-enhanced green fluorescent protein (Q97) undergo a protracted form of nonapoptotic death that is insensitive to Bax deletion or caspase inhibition but is characterized by mitochondrial dysfunction. By treating the neurons with combined cytosine arabinoside and NGF withdrawal, we demonstrate that Q97 confers a powerful resistance to apoptosis at multiple levels: despite normal proapoptotic signaling (elevation of P-ser15-p53 and BimEL), there is no increase of Puma mRNA or Bax activation, both necessary for apoptosis. Even restoration of Bax translocation with overexpressed Puma does not activate apoptosis. We demonstrate that this robust inhibition of apoptosis is caused by Q97-mediated accumulation of Hsp70, which occurs through inhibition of proteasomal activity. Thus, apoptosis is reinstated by short hairpin RNA-mediated knockdown of Hsp70. These findings explain the rarity of apoptotic death in Q97-expressing neurons. Given the...Continue Reading

Citations

Aug 21, 2013·Cell Death & Disease·J SassoneA Ciammola
Jul 29, 2011·Nucleic Acids Research·Agnieszka MykowskaWlodzimierz J Krzyzosiak
Dec 14, 2011·PloS One·Daniel F GilbertMichael Boutros
Feb 21, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Rona K GrahamMichael R Hayden
Apr 29, 2014·Cell Death and Differentiation·M Kristiansen, J Ham
May 26, 2010·The European Journal of Neuroscience·Rebecca LeonJianning Wei
Feb 20, 2016·Biological Chemistry·Panagiotis S AthanasopoulosRolf Heumann
Mar 20, 2010·Biochemical Society Transactions·Sarah L HandsAndreas Wyttenbach

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