Abnormal group I metabotropic glutamate receptor expression and signaling in the frontal cortex in Pick disease.
Group I metabotropic glutamate receptors (mGluR1) regulate synaptic transmission through the stimulation of phospholipase Cbeta1 (PLCbeta1) and then by the activation of protein kinase C (PKC). Considering these properties, it is conceivable that major cortical functional deficits may be attributed to abnormal mGluR processing and signaling. The present work examines mGluRI expression and signaling in the frontal cortex (area 8) of 3 cases with Pick disease (PiD), a neurodegenerative disease with abnormal phospho-tau accumulation, in comparison with 3 age-matched controls by means of glutamate binding assays, enzymatic activity, gel electrophoresis and Western blotting, solubility and immunoprecipitation assays, and confocal microscopy. Reduced expression levels of PLCbeta1 and reduced PLCbeta1 activity have been found in PiD. The expression levels of the nonrelated phospholipase PLCgamma, a substrate of tyrosine kinase, are also reduced in PiD. This is accompanied by a marked decrease in the expression of cPKCalpha and increased expression of the inner band (76 kDa) of the nPKCdelta doublet at the expense of a decrease of the phosphorylated (active) form (78 kDa). In contrast, L-[3H]glutamate-specific binding to mGluRs is augmented in PiD cases, mainly because of the higher mGluR1 and mGluRs expression levels detected. No modifications in PLCbeta1 solubility have been observed in PiD and no interactions between PLCbeta1 and tau have been demonstrated in diseased and control cases. Moreover, double-labeling immunofluorescence and confocal microscopy have shown no colocalization of phospho-tau (AT8 antibody) and PLCbeta1 in phospho-tau inclusions, including Pick bodies. These results demontrate for the first time abnormal mGluR signaling in the cerebral cortex in PiD and selective vulnerability of phospholipases and PKC to PiD.
Dalfó
Esther
E
Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Spain.
Albasanz
José Luis
JL
Rodríguez
Agustín
A
Martín
Mairena
M
Ferrer
Isidro
I
D000368:Aged; D015153:Blotting, Western; D005260:Female; D005455:Fluorescent Antibody Technique; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D054799:Phospholipase C beta; D051966:Phospholipase C gamma; D020774:Pick Disease of the Brain / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
D007527:Isoenzymes; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; C496628:PRKCA protein, human; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D010738:Type C Phospholipases; D054799:Phospholipase C beta; D051966:Phospholipase C gamma