In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 27, No. 50 ( 2007-12-12), p. 13614-13623
Abstract:
Expansion of a CAG repeat in the Huntington's disease (HD) gene results in progressive neuronal loss, particularly of striatal medium-sized spiny neurons (MSNs). Studies in human HD autopsy brain tissue, as well as cellular and animal models of HD, suggest that increased activity of NMDA-type glutamate receptors and altered mitochondrial function contribute to selective neuronal degeneration. In this regard, the YAC128 mouse model, expressing full-length human huntingtin with 128 glutamine repeats, has been the focus of much interest. Although NMDA-induced apoptosis is enhanced in YAC128 MSNs, here we report that the initial steps in the death signaling pathway, including NMDA receptor (NMDAR) current and cytosolic Ca 2+ loading, are similar to those observed in wild-type MSNs. In contrast, we found that the NMDAR-mediated Ca 2+ load triggered a strikingly enhanced loss of mitochondrial membrane potential in YAC128 MSNs, suggesting that NMDAR signaling via the mitochondrial apoptotic pathway is altered. This effect was accompanied by impaired cytosolic Ca 2+ clearance after removal of NMDA, a difference that was not apparent after high potassium-evoked depolarization-mediated Ca 2+ entry. Inhibition of the mitochondrial permeability transition (mPT) reduced peak cytosolic Ca 2+ and mitochondrial depolarization evoked by NMDA in YAC128 MSNs but not wild-type MSNs. Hence, in contrast to YAC models with moderate CAG expansions, the enhanced NMDA-induced apoptosis in YAC128 MSNs is predominantly determined by augmented mitochondrial sensitivity to Ca 2+ -induced activation of the mPT. These results suggest that the CAG repeat length influences the mechanism by which mHtt enhances NMDAR-mediated excitotoxicity.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.3455-07.2007
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2007
detail.hit.zdb_id:
1475274-8
SSG:
12
Permalink
