Neuronal Protein Farnesylation Regulates Hippocampal Synaptic Plasticity and Cognitive Function
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Neuronal Protein Farnesylation Regulates Hippocampal Synaptic Plasticity and Cognitive Function Wenhui Qu 1 & Kiall F. Suazo 2 & Wenfeng Liu 3 Li-Lian Yuan 4 & Mark D. Distefano 2 & Ling Li 1,3,5
&
Shaowu Cheng 3 & Angela Jeong 3 & David Hottman 3 &
Received: 8 July 2020 / Accepted: 12 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Keywords Protein prenylation . Farnesyltransferase . Small GTPases . Synaptic plasticity . Cognitive function . Prenylomics
Introduction Protein prenylation is an important post-translational modification that adds lipid molecules, isoprenoids, to
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02169-w) contains supplementary material, which is available to authorized users. * Ling Li [email protected] 1
Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA
2
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
3
Department of Experimental and Clinical Pharmacology, University of Minnesota, McGuire Translational Research Facility (MTRF) 4-208, 2001 6th Street SE, Minneapolis, MN 55455, USA
4
Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA 50312, USA
5
Graduate Program in Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
target proteins and governs a variety of cellular signaling pathways [1]. In the nervous system, protein prenylation mediates neurite outgrowth, dendritic morphology, and synaptic plast
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