Metabotropic glutamate receptor/phospholipase C pathway: A vulnerable target to Creutzfeldt-Jakob disease in the cerebral cortex

• Published in: Neuroscience 2005, Vol.131 (4), p.825-832
• Main Authors: Rodríguez, A., Freixes, M., Dalfó, E., Martín, M., Puig, B., Ferrer, I.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Blotting, Western; Brain - pathology; Brain Chemistry; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Creutzfeldt-Jakob disease; Creutzfeldt-Jakob Syndrome - metabolism; Creutzfeldt-Jakob Syndrome - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Electrophoresis, Polyacrylamide Gel; Female; Fundamental and applied biological sciences. Psychology; Humans; Immunoprecipitation; Isoenzymes - biosynthesis; Male; Medical sciences; metabotropic glutamate receptors; Middle Aged; Nerve Tissue Proteins - metabolism; Neurology; phospholipase C; Phospholipase C beta; prion diseases; Prions - chemistry; Prions - metabolism; protein kinase C; Protein Kinase C - biosynthesis; Protein Kinase C-alpha; Protein Kinase C-delta; Receptors, Metabotropic Glutamate - biosynthesis; Receptors, Metabotropic Glutamate - physiology; Type C Phospholipases - biosynthesis; Type C Phospholipases - physiology; Vertebrates: nervous system and sense organs
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2004.12.023

Glutamate is the main excitatory neurotransmitter in the cerebral cortex. Altered glutamatergic transmission has been suggested as having a central role in many neurodegenerative diseases. Metabotropic glutamate receptors (mGluRs) are coupled to intracellular signal transduction via G proteins, and they mediate slower responses than ionotropic glutamate receptors. Group I mGluRs are positively coupled to phospholipase C β1 (PLCβ 1). Creutzfeldt-Jakob disease (CJD) is a human transmissible spongiform encephalopathy associated with a dysfunction in the membrane glycoprotein PrP which is converted into an abnormal isoform, with a predominant β-sheet structure, that is pathogenic and partially resistant to protease digestion. Proteins associated with the signal transduction of group I mGluRs were examined in the frontal cortex (area 8) of 12 cases with sCJD and four age-matched controls, by means of gel electrophoresis and Western blotting of total homogenates. Densitometric analysis of the bands demonstrated decreased expression levels of PLCβ 1 and PLCγ, a non-related phospholipase which is a substrate of tyrosine kinase, in CJD cases when compared with controls. Novel protein kinase C δ (nPKCδ) has also been found to be significantly decreased in CJD cases. However, no modifications in mGluR 1 cPKCα expression levels are found in CJD when compared with controls. No modifications in PLCβ 1 solubility in PBS-, deoxycholate- and sodium dodecylsulphate-soluble fractions have been observed in CJD when compared with controls. Finally, no interactions between PLCβ1 and PrP, as revealed by immunoprecipitation assays, have been found in CJD and controls. The present results show, for the first time, reduced expression levels of phospholipases, particularly PLCβ 1, which may interfere with group I mGluR signaling in the cerebral cortex in CJD. These abnormalities are not the result of abnormal PLC solubility or interactions with PrP. Selective involvement of group I mGluRs may have functional effects on glutamatergic transmission modulation and processing in CJD.