Protein Prenylation and Synaptic Plasticity: Implications for Alzheimer’s Disease

Hottman, David A.; L, Li

doi:10.1007/s12035-013-8627-z

Cited by 55 publications

(46 citation statements)

References 88 publications

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“…These cocrystallized or conserved lipids are likely only the tip of the iceberg because the harsh conditions of the protein preparation during crystal preparation get rid of most lipids. Finally, lipidation or the process of covalently attaching lipid groups into membrane proteins, namely palmitoylation, and prenylation, affects numerous functions in the synapses [37,38].…”

Section: Synaptic Membrane Plays a Role In Neurotransmission?mentioning

confidence: 99%

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

Postila

Róg

2019

Mol Neurobiol

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Synaptic neurotransmission is generally considered as a function of membrane-embedded receptors and ion channels in response to the neurotransmitter (NT) release and binding. This perspective aims to widen the protein-centric view by including another vital component-the synaptic membrane-in the discussion. A vast set of atomistic molecular dynamics simulations and biophysical experiments indicate that NTs are divided into membrane-binding and membrane-nonbinding categories. The binary choice takes place at the water-membrane interface and follows closely the positioning of the receptors' binding sites in relation to the membrane. Accordingly, when a lipophilic NT is on route to a membrane-buried binding site, it adheres on the membrane and, then, travels along its plane towards the receptor. In contrast, lipophobic NTs, which are destined to bind into receptors with extracellular binding sites, prefer the water phase. This membrane-based sorting splits the neurotransmission into membraneindependent and membrane-dependent mechanisms and should make the NT binding into the receptors more efficient than random diffusion would allow. The potential implications and notable exceptions to the mechanisms are discussed here. Importantly, maintaining specific membrane lipid compositions (MLCs) at the synapses, especially regarding anionic lipids, affect the level of NT-membrane association. These effects provide a plausible link between the MLC imbalances and neurological diseases such as depression or Parkinson's disease. Moreover, the membrane plays a vital role in other phases of the NT life cycle, including storage and release from the synaptic vesicles, transport from the synaptic cleft, as well as their synthesis and degradation.

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Section: Synaptic Membrane Plays a Role In Neurotransmission?mentioning

confidence: 99%

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

Postila

Róg

2019

Mol Neurobiol

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“…AD is a chronic neurodegenerative syndrome caused by the appearance of brain senile plaques composed of aggregated forms of β-amyloid peptide (Aβ), and it is the most common cause of Catalysts 2019, 9, 260 6 of 32 dementia in elderly people, with a new case globally occurring every seven seconds [72]. Emerging evidence suggests a link between cholesterol and AD [37,[72][73][74][75][76], and extensive studies have been published stressing the therapeutic utility of pleiotropic effects of statins, showing a dose-dependent beneficial effect on cognition, memory, and neuroprotection [72] by different mechanisms, such as altering the properties of plasma membrane by a reduction in cholesterol levels and a modulation of secretase activities, thus decreasing amyloid precursor protein (APP) processing [77], or by altering neuronal activity via modification of GTPases prenylation [28,74,78]. On the other hand, a possible effect of statins in cholinergic neurotransmission has been also described; in fact, simvastatin inhibits acetyl cholinesterase (AChE) activity in rats [79] and prevents the blockade caused by AChE inhibitors at α 7-nicotinic AChE receptors [80], thus increasing cholinergic neurotransmission.…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

Biocatalyzed Synthesis of Statins: A Sustainable Strategy for the Preparation of Valuable Drugs

2019

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Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are the largest selling class of drugs prescribed for the pharmacological treatment of hypercholesterolemia and dyslipidaemia. Statins also possess other therapeutic effects, called pleiotropic, because the blockade of the conversion of HMG-CoA to (R)-mevalonate produces a concomitant inhibition of the biosynthesis of numerous isoprenoid metabolites (e.g., geranylgeranyl pyrophosphate (GGPP) or farnesyl pyrophosphate (FPP)). Thus, the prenylation of several cell signalling proteins (small GTPase family members: Ras, Rac, and Rho) is hampered, so that these molecular switches, controlling multiple pathways and cell functions (maintenance of cell shape, motility, factor secretion, differentiation, and proliferation) are regulated, leading to beneficial effects in cardiovascular health, regulation of the immune system, anti-inflammatory and immunosuppressive properties, prevention and treatment of sepsis, treatment of autoimmune diseases, osteoporosis, kidney and neurological disorders, or even in cancer therapy. Thus, there is a growing interest in developing more sustainable protocols for preparation of statins, and the introduction of biocatalyzed steps into the synthetic pathways is highly advantageous-synthetic routes are conducted under mild reaction conditions, at ambient temperature, and can use water as a reaction medium in many cases. Furthermore, their high selectivity avoids the need for functional group activation and protection/deprotection steps usually required in traditional organic synthesis. Therefore, biocatalysis provides shorter processes, produces less waste, and reduces manufacturing costs and environmental impact. In this review, we will comment on the pleiotropic effects of statins and will illustrate some biotransformations nowadays implemented for statin synthesis.

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“…6 Post-translational lipid modifications include the enzymatic addition of an isoprenyl group such as farnesyl or geranylgeranyl (collectively called prenylation), or a fatty acid moiety, such as a palmitoyl or myristoyl group. Dysregulated lipid modifications of proteins have been implicated in neuropsychiatric disorders, including Alzheimer's disease, 7 Huntington's disease, 8,9 and in a mouse model of schizophrenia. 10 Abnormal lipid modifications have been reported in schizophrenia in dorsolateral prefrontal cortex (DLPFC), including decreased protein S-palmitoylation 11 and altered levels of a key N-myristoylated protein.…”

Section: Introductionmentioning

confidence: 99%

Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex

Pinner

Mueller

Alganem

et al. 2019

Preprint

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The pathophysiology of schizophrenia includes altered neurotransmission, dysregulated intracellular signaling pathway activity, and abnormal dendritic morphology that contribute to deficits of synaptic plasticity in the disorder. These processes all require dynamic protein-protein interactions at cell membranes. Lipid modifications target proteins to membranes by increasing substrate hydrophobicity by the addition of a fatty acid or isoprenyl moiety, and recent evidence suggests that dysregulated posttranslational lipid modifications may play a role in multiple neuropsychiatric disorders including schizophrenia. Consistent with these emerging findings, we have recently reported decreased protein S-palmitoylation in schizophrenia. Protein prenylation is a lipid modification that occurs upstream of Spalmitoylation on many protein substrates, facilitating membrane localization and activity of key intracellular signaling proteins. Accordingly, we hypothesized that in addition to palmitoylation, protein prenylation may be abnormal in schizophrenia. To test this, we assayed protein expression of the five prenyltransferase subunits (FNTA, FNTB, PGGT1B, RABGGTA, and RABGGTB) in postmortem dorsolateral prefrontal cortex from patients with schizophrenia and paired comparison subjects (N = 13 pairs). We found decreased levels of FNTA (14%), PGGT1B (13%), and RABGGTB (8%) in schizophrenia. To determine if upstream or downstream factors may be driving these changes, we also assayed protein expression of the isoprenoid synthases FDPS and GGPS1, and prenylation-dependent processing enzymes REC and ICMT. We found these upstream and downstream enzymes to have normal protein expression. To rule out effects from chronic antipsychotic treatment, we assayed FNTA, PGGT1B and RABGGTB in cortex from rats treated long-term with haloperidol decanoate, and found no change in the expression of these proteins. Given the role prenylation plays in localization of key signaling proteins found at the synapse, these data offer a potential mechanism underlying abnormal protein-protein interactions and protein localization in schizophrenia.

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Protein Prenylation and Synaptic Plasticity: Implications for Alzheimer’s Disease

Cited by 55 publications

References 88 publications

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

Biocatalyzed Synthesis of Statins: A Sustainable Strategy for the Preparation of Valuable Drugs

Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex

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