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. 2006 Apr 5;14(4):388–398. doi: 10.1111/j.1750-3639.2004.tb00082.x

Abnormal Metabotropic Glutamate Receptor Expression and Signaling in the Cerebral Cortex in Diffuse Lewy Body Disease is Associated with Irregular α‐Synuclein/Phospholipase C (PLCβ1) Interactions

E Dalfó 1, J L Albasanz 3, M Martín 3, I Ferrer 1,2,✉
PMCID: PMC8095885  PMID: 15605986

Abstract

Diffuse Lewy body disease (DLBD) is a degenerative disease of the nervous system, involving the brain stem, diencephalic nuclei and cerebral cortex, associated with abnormal α‐synuclein aggregation and widespread formation of Lewy bodies and Lewy neurites. DLBD presents as pure forms (DLBDp) or in association with Alzheimer disease (AD) in the common forms (DLBDc). Several neurotransmitter abnormalities have been reported including those of the nigrostriatal and mesocorticolimbic dopaminergic system, and central noradrenergic, serotoninergic and cholinergic pathways. The present work examines metabotropic glutamate receptor (mGluR) expression and signaling in the frontal cortex of DLBDp and DLBDc cases in comparison with age‐matched controls. Abnormal L‐[3H]glutamate specific binding to group I and II mGluRs, and abnormal mGluR1 levels have been found in DLBD. This is associated with reduced expression levels of phospholipase C β1 (PLCβ1), the effector of group I mGluRs following protein G activation upon glutamate binding. Additional modification in the solubility of PLCβ1 and reduced PLCβ1 activity in pure and common DLBD further demonstrates for the first time abnormal mGluR signaling in the cerebral cortex in DLBD. In order to look for a possible link between abnormal mGluR signaling and α‐synuclein accumulation in DLBD, immunoprecipitation studies have shown α‐synuclein/PLCβ1 binding in controls and decreased α‐synuclein/PLCβ1 binding in DLBD. This is accompanied by a shift in the distribution of α‐synuclein, but not of PLCβ1, in DLBD when compared with controls. Together, these results support the concept that abnormal α‐synuclein in DLBD produces functional effects on cortical glutamatergic synapses, which are associated with reduced α‐synuclein/PLCβ1 interactions, and, therefore, that mGluRs are putative pharmacological targets in DLBD. Finally, these results emphasize the emergence of a functional neuropathology that has to be explored for a better understanding of the effects of abnormal protein interactions in degenerative diseases of the nervous system.

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