Title

Antiapoptotic protein Lifeguard is required for survival and maintenance of Purkinje and granular cells

Authors

Tatiana Hurtado de Mendoza, The Salk Institute for Biological Studies
Carlos G. Perez-Garcia, The Salk Institute for Biological Studies
Todd T. Kroll, Central Washington UniversityFollow
Nien H. Hoong, The Salk Institute for Biological Sciences
Dennis D. M. O'Leary, The Salk Institute for Biological Sciences
Inder M. Verma, The Salk Institute for Biological Sciences

Document Type

Article

Department or Administrative Unit

Chemistry

Publication Date

10-11-2011

Abstract

Lifeguard (LFG) is an inhibitor of Fas-mediated cell death and is highly expressed in the cerebellum. We investigated the biological role of LFG in the cerebellum in vivo, using mice with reduced LFG expression generated by shRNA lentiviral transgenesis (shLFG mice) as well as LFG null mice. We found that LFG plays a role in cerebellar development by affecting cerebellar size, internal granular layer (IGL) thickness, and Purkinje cell (PC) development. All these features are more severe in early developmental stages and show substantial recovery overtime, providing a remarkable example of cerebellar plasticity. In adult mice, LFG plays a role in PC maintenance shown by reduced cellular density and abnormal morphology with increased active caspase 8 and caspase 3 immunostaining in shLFG and knockout (KO) PCs. We studied the mechanism of action of LFG as an inhibitor of the Fas pathway and provided evidence of the neuroprotective role of LFG in cerebellar granule neurons (CGNs) and PCs in an organotypic cerebellar culture system. Biochemical analysis of the Fas pathway revealed that LFG inhibits Fas-mediated cell death by interfering with caspase 8 activation. This result is supported by the increased number of active caspase 8-positive PCs in adult mice lacking LFG. These data demonstrate that LFG is required for proper development and survival of granular and Purkinje cells and suggest LFG may play a role in cerebellar disorders.

Comments

This article was originally published in Proceedings of the National Academy of Sciences. The full-text article from the publisher can be found here.

Due to copyright restrictions, this article is not available for free download from ScholarWorks @ CWU.

Recommended Citation

Hurtado de Mendoza, T., Perez-Garcia, C. G., Kroll, T. T., Hoong, N. H., O’Leary, D. D. M., & Verma, I. M. (2011). Antiapoptotic protein Lifeguard is required for survival and maintenance of Purkinje and granular cells. Proceedings of the National Academy of Sciences, 108(41), 17189–17194. https://doi.org/10.1073/pnas.1114226108

Journal

Proceedings of the National Academy of Sciences

Rights

© 2011 the authors.