Topic
PCP4
About: PCP4 is a research topic. Over the lifetime, 28 publications have been published within this topic receiving 934 citations. The topic is also known as: PEP-19 & Purkinje cell protein 4.
Papers
TL;DR: In this paper, RNA-targeted therapies were tested in two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease.
Abstract: There are no disease-modifying treatments for adult human neurodegenerative diseases. Here we test RNA-targeted therapies in two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease. Both models recreate the progressive adult-onset dysfunction and degeneration of a neuronal network that are seen in patients, including decreased firing frequency of cerebellar Purkinje cells and a decline in motor function. We developed a potential therapy directed at the ATXN2 gene by screening 152 antisense oligonucleotides (ASOs). The most promising oligonucleotide, ASO7, downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. These findings support ASOs as a promising approach for treating some human neurodegenerative diseases.
294 citations
TL;DR: A custom ferret cDNA microarray designed to reveal patterns of gene expression in the visual thalamus correlated with physiological processing streams reveals a rich molecular repertoire that correlates with functional divisions of the lateral geniculate nucleus of the primate LGN.
Abstract: The visual system encodes and deciphers information using parallel, anatomically segregated, processing streams. To reveal patterns of gene expression in the visual thalamus correlated with physiological processing streams, we designed a custom ferret cDNA microarray. By isolating specific subregions and layers of the thalamus, we identified a set of transcription factors, including Zic2, Islet1, and Six3, the unique distribution profiles of which differentiated the lateral geniculate nucleus (LGN) from the associated perigeniculate nucleus. Within the LGN, odd homeobox1 differentiated the A layers, which contain X cells and Y cells, from the C layers. One neuron-specific protein, Purkinje cell protein 4 (PCP4), was strongly expressed in Y cells in the ferret LGN and in the magnocellular layers of the primate LGN. In the ferret LGN, PCP4 expression began as early as postnatal day 7 (P7), suggesting that Y cells are already specified by P7. These results reveal a rich molecular repertoire that correlates with functional divisions of the LGN.
87 citations
TL;DR: The data indicate that pep-19/pcp4 is a critical determinant of synaptic plasticity in cerebellum and locomotor learning.
Abstract: PEP-19/PCP4 maps within the Down syndrome critical region and encodes a small, predominantly neuronal, IQ motif protein. Pep-19 binds calmodulin and inhibits calmodulin-dependent signaling, which is critical for synaptic function, and therefore alterations in Pep-19 levels may affect synaptic plasticity and behavior. To investigate its possible role, we generated and characterized pep-19/pcp4-null mice. Synaptic plasticity at excitatory synapses of cerebellar Purkinje cells, which express the highest levels of Pep-19, was dramatically altered in pep-19/pcp4-null mice. Instead of long-term depression, pep-19/pcp4-null mice exhibited long-term potentiation at parallel fiber-Purkinje cell synapses. The mutant mice have a marked deficit in their ability to learn a locomotor task, as measured by improved performance upon repeated testing on an accelerating rotarod. Thus, our data indicate that pep-19/pcp4 is a critical determinant of synaptic plasticity in cerebellum and locomotor learning.
75 citations
TL;DR: It is shown that mossy fiber sprouting also targets CA2 pyramidal cell somata and that the CA2 region undergoes prominent structural reorganization under epileptic conditions, calling attention to CA2 as a region affected by MTLE‐associated pathological restructuring.
Abstract: Dentate granule cells and the hippocampal CA2 region are resistant to cell loss associated with mesial temporal lobe epilepsy (MTLE). It is known that granule cells undergo mossy fiber sprouting in the dentate gyrus which contributes to a recurrent, proepileptogenic circuitry in the hippocampus. Here it is shown that mossy fiber sprouting also targets CA2 pyramidal cell somata and that the CA2 region undergoes prominent structural reorganization under epileptic conditions. Using the intrahippocampal kainate mouse model for MTLE and the CA2-specific markers Purkinje cell protein 4 (PCP4) and regulator of G-Protein signaling 14 (RGS14), it was found that during epileptogenesis CA2 neurons survive and disperse in direction of CA3 and CA1 resulting in a significantly elongated CA2 region. Using transgenic mice that express enhanced green fluorescent protein (eGFP) in granule cells and mossy fibers, we show that the recently described mossy fiber projection to CA2 undergoes sprouting resulting in aberrant large, synaptoporin-expressing mossy fiber boutons which surround the CA2 pyramidal cell somata. This opens up the potential for altered synaptic transmission that might contribute to epileptic activity in CA2. Indeed, intrahippocampal recordings in freely moving mice revealed that epileptic activity occurs concomitantly in the dentate gyrus and in CA2. Altogether, the results call attention to CA2 as a region affected by MTLE-associated pathological restructuring.
67 citations
TL;DR: Identification of the CA2 region in the mouse by immunostaining with a Purkinje cell protein 4 (PCP4) antibody, which effectively delineates CA3/CA2 and CA2/CA1 borders and agrees well with previous cytoarchitectural definitions of CA2.
Abstract: The hippocampal CA2 subfield was initially identified by Lorente de No as an anatomically distinct region based on its cytoarchitectural features. Although there is an enormous body of literature on other hippocampal subfields (CA1 and CA3), relatively little is known about the physiological and developmental properties of CA2. Here we report identification of the CA2 region in the mouse by immunostaining with a Purkinje cell protein 4 (PCP4) antibody, which effectively delineates CA3/CA2 and CA2/CA1 borders and agrees well with previous cytoarchitectural definitions of CA2. The PCP4 immunostaining–delineated CA2 neurons have distinguishable differences in cell morphology, physiology, and synaptic circuit connections compared with distal CA3 and proximal CA1 regions. The average somatic sizes of excitatory cells differ across CA1–3, with the smallest to largest somatic size being CA1
63 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 1 |
| 2020 | 1 |
| 2019 | 3 |
| 2017 | 1 |
| 2016 | 1 |
| 2015 | 2 |