Title

Alterations in mGluR5 Expression and Signaling in Lewy Body Disease and in Transgenic Models of Alpha- Synucleinopathy – Implications for Excitotoxicity

Author Info

Diana L. Price, University of California - San Diego
Edward Rockenstein, University of California - San Diego
Kiran Ubhi, University of California - San Diego
Van Phung, University of California - San Diego
Natalie MacLean-Lewis, University of California - San Diego
David A. Askay, University of California - San DiegoFollow
Anna Cartier, University of California - San Diego
Brian Spencer, University of California - San Diego
Christina Patrick, University of California - San Diego
Paula Desplats, University of California - San Diego
Mark H. Ellisman, University of California - San Diego
Eliezer Masliah, University of California - San Diego

Recommended Citation

Published in PLOS One, Volume 5, Issue 11, November 16, 2010, pages 1-16.

NOTE: At the time of publication, the author David Askay was not yet affiliated with Cal Poly.

The definitive version is available at https://doi.org/10.1371/journal.pone.0014020.

Abstract

Dementia with Lewy bodies (DLB) and Parkinson’s Disease (PD) are neurodegenerative disorders of the aging population characterized by the abnormal accumulation of alpha-synuclein (alpha-syn). Previous studies have suggested that excitotoxicity may contribute to neurodegeneration in these disorders, however the underlying mechanisms and their relationship to alpha-syn remain unclear. For this study we proposed that accumulation of alpha-syn might result in alterations in metabotropic glutamate receptors (mGluR), particularly mGluR5 which has been linked to deficits in murine models of PD. In this context, levels of mGluR5 were analyzed in the brains of PD and DLB human cases and alpha-syn transgenic (tg) mice and compared to age-matched, unimpaired controls, we report a 40% increase in the levels of mGluR5 and beta-arrestin immunoreactivity in the frontal cortex, hippocampus and putamen in DLB cases and in the putamen in PD cases. In the hippocampus, mGluR5 was more abundant in the CA3 region and co-localized with alpha-syn aggregates. Similarly, in the hippocampus and basal ganglia of alpha-syn tg mice, levels of mGluR5 were increased and mGluR5 and alpha-syn were co-localized and co-immunoprecipated, suggesting that alpha-syn interferes with mGluR5 trafficking. The increased levels of mGluR5 were accompanied by a concomitant increase in the activation of downstream signaling components including ERK, Elk-1 and CREB. Consistent with the increased accumulation of alpha-syn and alterations in mGluR5 in cognitive- and motor-associated brain regions, these mice displayed impaired performance in the water maze and pole test, these behavioral alterations were reversed with the mGluR5 antagonist, MPEP. Taken together the results from study suggest that mGluR5 may directly interact with alpha-syn resulting in its over activation and that this over activation may contribute to excitotoxic cell death in select neuronal regions. These results highlight the therapeutic importance of mGluR5 antagonists in alpha-synucleinopathies.

Disciplines

Communication

Copyright

2010 Price, Rockenstein, Ubhi, Phung, MacLean-Lewis, Askay, Cartier, Spencer, Patrick, Desplats, Ellisman, Masliah.

Publisher statement

This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.