Protein prenylation is a post-translational lipid modification that governs a variety of important cellular signaling pathways, including those regulating synaptic functions and cognition in the nervous system. Two enzymes, farnesyltransferase (FT) and geranylgeranyltransferase type I (GGT), are essential for the prenylation process. Genetic reduction of FT or GGT ameliorates neuropathology but only FT haplodeficiency rescues cognitive function in transgenic mice of Alzheimer’s disease. A follow-up study showed that systemic or forebrain neuron-specific deficiency of GGT leads to synaptic and cognitive deficits under physiological conditions. Whether FT plays different roles in shaping neuronal functions and cognition remains elusive. This study shows that in contrast to the detrimental effects of GGT reduction, systemic haplodeficiency of FT has little to no impact on hippocampal synaptic plasticity and cognition. However, forebrain neuron-specific FT deletion also leads to reduced synaptic plasticity, memory retention, and hippocampal dendritic spine density. Furthermore, a novel prenylomic analysis identifies distinct pools of prenylated proteins that are affected in the brain of forebrain neuron-specific FT and GGT knockout mice, respectively. Taken together, this study uncovers that physiological levels of FT and GGT in neurons are essential for normal synaptic/cognitive functions and that the prenylation status of specific signaling molecules regulates neuronal functions.
Bibliographical noteFunding Information:
This work was supported in part by grants from the National Institute on Aging of the National Institutes of Health (AG056976 and AG058081), National Institute of General Medical Science (R01GM084152), the National Institute of Neurological Disorders and Stroke (R01NS107442), and the National Science Foundation (CHE-1308655). KFS was supported by a Doctoral Dissertation Fellowship from the University of Minnesota. Acknowledgments
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- Cognitive function
- Protein prenylation
- Small GTPases
- Synaptic plasticity
PubMed: MeSH publication types
- Journal Article