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- Title
Reevaluation of Neurodegeneration in lurcher Mice: Constitutive Ion Fluxes Cause Cell Death with, Not by, Autophagy.
- Authors
Nishiyama, Jun; Matsuda, Keiko; Kakegawa, Wataru; Yamada, Nobuaki; Motohashi, Junko; Mizushima, Noboru; Yuzaki, Michisuke
- Abstract
The lurcher (Lc) mice have served as a valuable model for neurodegeneration for decades. Although the responsible mutation was identified in genes encoding δ2 glutamate receptors (GluD2s), which are predominantly expressed in cerebellar Purkinje cells, how the mutant receptor (GluD2Lc) triggers cell death has remained elusive. Here, taking advantage of recent knowledge about the domain structure of GluD2, we reinvestigated Lc-mediated cell death, focusing on the "autophagic cell death" hypothesis. Although autophagy and cell death were induced by the expression of GluD2δ in heterologous cells and cultured neurons, they were blocked by the introduction of mutations in the channel pore domain of GluD2δ or by removal of extracellular Na+. In addition, although GluD2δ is reported to directly activate autophagy, mutant channels that are not associated with n-PIST (neuronal isoform of protein-interacting specifically with TC10)-Beclin1 still caused autophagy and cell death. Furthermore, cells expressing GluD2δ showed decreased ATP levels and increased AMP-activated protein kinase(AMPK)activities in a manner dependent on extracellular Na+. Thus, constitutive currents were likely necessary and sufficient to induce autophagy viaAMPKactivation, regardless of the n-PIST-Beclin1 pathway in vitro. Interestingly, the expression of dominant-negative AMPK suppressed GluD2Lc-induced autophagy but did not prevent cell death in heterologous cells. Similarly, the disruption of Atg5, a gene crucial for autophagy, did not prevent but rather aggravated Purkinje-cell death in Lc mice. Furthermore, calpains were specifically activated in Lc Purkinje cells. Together, these results suggest that Lc-mediated cell death was not caused by autophagy but necrosis with autophagic features both in vivo and in vitro.
- Subjects
NEURODEGENERATION; LABORATORY mice; CELL death; LURCHER; PURKINJE cells; NEURONS
- Publication
Journal of Neuroscience, 2010, Vol 30, Issue 6, p2177
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.6030-09.2010