Impaired geranylgeranyltransferase‐I regulation reduces membrane‐associated Rho protein levels in aged mouse brain

Afshordel, Sarah; Wood, W. Gibson; Igbavboa, Urule; Müller, Walter E.; Eckert, Gunter P.

doi:10.1111/jnc.12654

Cited by 31 publications

(32 citation statements)

References 67 publications

(123 reference statements)

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“…Age-related downregulation of PGGT1B in mice is associated with decreased membrane-associated Rho-GTPases involved in synaptic plasticity. Inhibition of GGTase I in vitro leads to decreased protein levels of synaptophysin and GAP-43, 59 and these proteins are also decreased in schizophrenia brain. [60][61][62] Studies using statins, which inhibit the activity of the mevalonate pathway that produces FPP and GGPP, and prenylation-specific inhibitors in neuronal cultures, have reported decreased dendritic aborization 63,64 and increased axonal growth.…”

Section: Discussionmentioning

confidence: 98%

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.

show abstract

Section: Discussionmentioning

confidence: 98%

Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex

Pinner

Mueller

Alganem

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Agerelated downregulation of PGGT1B in mice is associated with decreased membrane-associated Rho-GTPases involved in synaptic plasticity. Inhibition of GGTase I in vitro leads to decreased protein levels of synaptophysin and GAP-43 59 , and these proteins are also decreased in schizophrenia brain [60][61][62] . Studies using statins, which inhibit the activity of the mevalonate pathway that produces FPP and GGPP, and prenylation-specific inhibitors in neuronal cultures, have reported decreased dendritic aborization 63,64 and increased axonal growth 65,66 .…”

Section: Discussionmentioning

confidence: 98%

Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex

et al. 2020

View full text Add to dashboard Cite

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 S-palmitoylation 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 whether 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 RCE 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 the 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.

show abstract

“…While many of these works implicate altered protein geranylgeranylation as an important mechanistic component, the roles of individual geranylgeranylated proteins need to be further defined. This work would help to elucidate additional consequences of the observed decrease in activity of geranylgeranyl transferase I and the roles of individual geranylgeranylated proteins in aging and neurodegenerative disorders [33].…”

Section: Discussionmentioning

confidence: 99%

Non-prenylatable, cytosolic Rac1 alters neurite outgrowth while retaining the ability to be activated

Reddy

Samuel

McConnell

et al. 2015

Cellular Signalling

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Impaired geranylgeranyltransferase‐I regulation reduces membrane‐associated Rho protein levels in aged mouse brain

Cited by 31 publications

References 67 publications

Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex

Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex

Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex

Non-prenylatable, cytosolic Rac1 alters neurite outgrowth while retaining the ability to be activated

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