Abstract
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.
Highlights
Altered neurotransmission is central to the pathophysiology of schizophrenia
Prenyltransferase subunits are abnormally expressed in schizophrenia We found that each prenyltransferase enzyme had decreased expression of either or both of its respective α and β subunits in schizophrenia relative to comparison subjects
We assayed FNTA, PGGT1B, and RABGGTB in rats chronically treated with haloperidol decanoate and found that haloperidol treatment did not affect the expression of these proteins in these rats (Fig. 2)
Summary
Altered neurotransmission is central to the pathophysiology of schizophrenia. Normal neurotransmission depends on regulation of receptor membrane localization and protein–protein interactions that regulate intracellular signaling activity[1,2]. Posttranslational modifications (PTMs), including lipid modification of proteins, have been shown to regulate neuronal functions and intracellular pathways by facilitating dynamic protein–protein interactions at membranes[3,4,5]. Altered posttranslational lipid modifications may mechanistically contribute to intracellular signaling abnormalities reported in schizophrenia[6]. Posttranslational 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
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