Isoprenoids and protein prenylation: implications in the pathogenesis and therapeutic intervention of Alzheimer’s disease

Abstract

The mevalonate-isoprenoid-cholesterol biosynthesis pathway plays a key role in human health and disease. The importance of this pathway is underscored by the discovery that two major isoprenoids, farnesyl and geranylgeranyl pyrophosphate, are required to modify an array of proteins through a process known as protein prenylation, catalyzed by prenyltransferases. The lipophilic prenyl group facilitates the anchoring of proteins in cell membranes, mediating protein-protein interactions and signal transduction. Numerous essential intracellular proteins undergo prenylation, including most members of the small GTPase superfamily as well as heterotrimeric G proteins and nuclear lamins, and are involved in regulating a plethora of cellular processes and functions. Dysregulation of isoprenoids and protein prenylation is implicated in various disorders, including cardiovascular and cerebrovascular diseases, cancers, bone diseases, infectious diseases, progeria, and neurodegenerative diseases including Alzheimer's disease (AD). Therefore, isoprenoids and/or prenyltransferases have emerged as attractive targets for developing therapeutic agents. Here, we provide a general overview of isoprenoid synthesis, the process of protein prenylation and the complexity of prenylated proteins, and pharmacological agents that regulate isoprenoids and protein prenylation. Recent findings that connect isoprenoids/protein prenylation with AD are summarized and potential applications of new prenylomic technologies for uncovering the role of prenylated proteins in the pathogenesis of AD are discussed.

Evaluation of musculoskeletal phenotype of the G608G progeria mouse model with lonafarnib, pravastatin, and zoledronic acid as treatment groups

“…Although FTIs have been previously shown to increase mean survival in HGPS patients (23)(24)(25), alternative prenylation events of progerin upstream of its farnesylation step were previously described, and can still occur in the presence of FTIs. Protein prenylation consists of the addition of farnesyl or geranylgeranyl groups on specific cysteine residues located near the C termini of various proteins (26). Alternative posttranslational prenylation of progerin (and subsequent accumulation) can occur by the action of the geranylgeranlyltransferase I (GGT-type I) protein.…”

Optimization of Metabolic Labeling with Alkyne-Containing Isoprenoid Probes

“…Prenylation facilitates protein localization mainly to the plasma membrane where the prenylated proteins including small GTPases mediate signal transduction pathways [10]. Changes in the level of prenylated proteins may be critical in a variety of diseases including Parkinson’s disease [11], Alzheimer’s disease [12], neurodegeneration [13], viral infections [14], and some type of cancers [15].…”

Combined Comparative Genomics and Gene Expression Analyses Provide Insights into the Terpene Synthases Inventory in Trichoderma

“…We found a large group of PTs, identified as squalene synthases (SQSs) (Pfam 00494; PTHR11626:SF2; PS01044) (orange color in Figure 1 ), showing the conserved TM helix region of 23 residues in their C-terminal [ 88 ], and enzymes involved in protein prenylation [ 89 ] (red color in Figure 1 ), such as type I geranylgeranyl transferases (GGTases 1) (PTHR11774:SF4), type II geranylgeranyl transferases (GGTases 2) (PTHR11774:SF11) and farnesyl transferases (FTases) (PTHR11774:SF6). They are present in single copy in the genomes of Trichoderma , but the additional SQS found in T. pleuroti indicates that at least one SQS is probably pathway-specific ( Table S4 ).…”