ABSTRACT
Deficits in hippocampal synaptic plasticity result in cognitive impairment in Huntington's disease (HD). Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that exerts neuroprotective actions, mainly through the PAC1 receptor. However, the role of PACAP in cognition is poorly understood, and no data exists in the context of Huntington's disease (HD). Here, we investigated the ability of PACAP receptor stimulation to enhance memory development in HD. First, we observed a hippocampal decline of all three PACAP receptor expressions, i.e., PAC1, VPAC1, and VPAC2, in two different HD mouse models, R6/1 and HdhQ7/Q111, from the onset of cognitive dysfunction. In hippocampal post-mortem human samples, we found a specific decrease of PAC1, without changes in VPAC1 and VPAC2 receptors. To determine whether activation of PACAP receptors could contribute to improve memory performance, we conducted daily intranasal administration of PACAP38 to R6/1 mice at the onset of cognitive impairment for seven days. We found that PACAP treatment rescued PAC1 level in R6/1 mice, promoted expression of the hippocampal brain-derived neurotrophic factor, and reduced the formation of mutant huntingtin aggregates. Furthermore, PACAP administration counteracted R6/1 mice memory deficits as analyzed by the novel object recognition test and the T-maze spontaneous alternation task. Importantly, the effect of PACAP on cognitive performance was associated with an increase of VGlut-1 and PSD95 immunolabeling in hippocampus of R6/1 mice. Taken together, these results suggest that PACAP, acting through stimulation of PAC1 receptor, may have a therapeutic potential to counteract cognitive deficits induced in HD.
Subject(s)
Hippocampus/physiopathology , Huntington Disease/physiopathology , Memory/physiology , Neuronal Plasticity/drug effects , Pituitary Adenylate Cyclase-Activating Polypeptide/pharmacology , Administration, Intranasal , Animals , Brain-Derived Neurotrophic Factor/metabolism , Cognition Disorders/physiopathology , Disease Models, Animal , Disks Large Homolog 4 Protein/metabolism , Gene Expression Regulation/drug effects , Hippocampus/pathology , Humans , Huntingtin Protein/metabolism , Male , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , Pituitary Adenylate Cyclase-Activating Polypeptide/administration & dosage , Protein Aggregates , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Vesicular Glutamate Transport Protein 1/metabolismSubject(s)
Antibodies/blood , Brain/metabolism , Encephalitis/blood , Encephalitis/immunology , Receptors, AMPA/immunology , Aged , Brain/pathology , Brain/physiopathology , Cell Line, Transformed , Encephalitis/drug therapy , Encephalitis/pathology , Female , Humans , Middle Aged , Transfection/methodsABSTRACT
Dysregulation of gene expression is one of the mechanisms involved in the pathophysiology of Huntington's disease (HD). Here, we examined whether mutant huntingtin regulates the levels of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1), a phosphatase that specifically dephosphorylates Akt at Ser473. Our results show decreased PHLPP1 protein levels in knock-in models (Hdh(Q111/Q111) mouse striatum and STHdh(Q111/Q111) cells), in the striatum of N-terminal exon-1 mutant huntingtin transgenic mouse models (R6/1; R6/1 : BDNF + or - , R6/2 and Tet/HD94) and in the putamen of HD patients. Quantitative PCR analysis revealed a reduction in PHLPP1 mRNA levels in the striatum of R6/1 compared with wild-type mice. Coincident with reduced PHLPP1 protein levels, we observed increased phosphorylated Akt (Ser473) levels specifically in the striatum. The analysis of the conditional mouse model Tet/HD94 disclosed that after mutant huntingtin shutdown PHLPP1 levels returned to wild-type levels whereas phospho-Akt levels were partially reduced. In conclusion, our results show that mutant huntingtin downregulates PHLPP1 expression. In the striatum, these reduced levels of PHLPP1 can contribute to maintain high levels of activated Akt that may delay cell death and allow the recovery of neuronal viability after mutant huntingtin silencing.
Subject(s)
Corpus Striatum/enzymology , Huntington Disease/enzymology , Nuclear Proteins/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphoprotein Phosphatases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Adult , Aged , Animals , Cell Death/physiology , Cell Line, Transformed , Cell Nucleus/metabolism , Corpus Striatum/pathology , Cytosol/metabolism , Disease Models, Animal , Exons/genetics , Female , Gene Knock-In Techniques , Humans , Huntington Disease/genetics , Huntington Disease/pathology , Male , Mice , Mice, Transgenic , Middle Aged , Neurotoxins/metabolism , Nuclear Proteins/chemistry , Nuclear Proteins/genetics , Phosphoprotein Phosphatases/chemistry , Phosphoprotein Phosphatases/genetics , Phosphorylation/physiology , Protein Structure, TertiaryABSTRACT
Antibodies against neuronal surface antigens (NSA-ab) have been described in pediatric opsoclonus-myoclonus syndrome (OMS). We analyzed the presence of NSA-ab by flow cytometry and immunocytochemistry of live cerebellar granular neurons (CGN) in the serum of 25 adult patients with idiopathic (14) and paraneoplastic (11) OMS. Paraneoplastic, but not idiopathic, OMS sera showed a CGN surface binding by flow cytometry higher than that of controls (mean MFI (median fluorescence intensity): 29+/-6.9 vs. 20+/-5.8; p=0.001) but only one serum had a binding greater than three standard deviations of controls. OMS sera did not label live CGN by immunocytochemistry. Unlike pediatric OMS, NSA-ab were not detected in adult cases suggesting that the immunity to NSA in OMS is heterogeneous.
