Abstract:
:The mechanisms by which polyglutamine expansion causes common features of neuronal death remain unclear. Here we describe an approach for delivering polyglutamine expansions directly into cultured sympathetic neurons. Glutamine (Q) residues (n = 10, 22, 30) were conjugated with a peptide possessing translocation properties across plasma membranes (PDP) and a nuclear localization signal (NLS). These peptides were rapidly incorporated into sympathetic neurons and showed neurotoxicity in a length- and dose-dependent manner. A robust induction of c-jun and cyclin D1 occurred following treatment with PDP-Q22-NLS. Enhanced c-Jun phosphorylation showed c-Jun N-terminal kinase (JNK) activation. Coincidentally, TrkA tyrosine phosphorylation was decreased in association with loss of phospho-Akt, the downstream target of PI-3 kinase. Despite such proapoptotic signals, neither release of cytochrome c from mitochondria nor caspase-3/7 activation was detected. TdT-mediated dUTP nick-end labeling-positive nuclear condensation, but no fragmentation, occurred. At 24 hr of treatment, cytoplasmic Ca2+ levels began to become elevated, and the cellular level of ATP was decreased. Cytoplasmic Ca2+ responses to KCl depolarization displayed a delayed recovery, providing evidence for lack of Ca2+ homeostasis. The neurons became committed to death at about 36 hr when mitochondrial Ca2+ uptake declined concurrently with loss of mitochondrial membrane potential. Collectively, these results show that, despite induction of early apoptotic signals, nonapoptotic neuronal cell death occurred via perturbed Ca2+ homeostasis and suggest that mitochondrial permeability transition may play important roles in this model of neuronal death.
journal_name
J Neurosci Resjournal_title
Journal of neuroscience researchauthors
Suzuki M,Koike Tdoi
10.1002/jnr.20461keywords:
subject
Has Abstractpub_date
2005-05-15 00:00:00pages
549-61issue
4eissn
0360-4012issn
1097-4547journal_volume
80pub_type
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