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Analysis of Two Novel Familial Alzheimer's Disease Genes
Wasco, Wilma M. 한림대학교 한림과학원 부설 환경ㆍ생명과학연구소 1995 국제학술회의 Vol.1995 No.-
Alzheimer's disease(AD) is a progressive neurodegenerative disorder that is characterized by dramatic personality changes and global cognitive decline. Although the pathogenic events that lead to the synaptic loss associated with the disease are not yet fully understood, it is clear that a significant portion of AD cases involve a genetic etiology. To date, genetic studies have suggested that loci on at least four different chromosomes play a role in AD, and it now know that mutations in three of these genes(located on Chromosomes 1,14 and 21) directly cause early-onset, autosomal dominantly inherited forms of familial AD(FAD), while a specific allele of a forth gene(located on Chromosome 19) appears to confirm susceptibility to late-onset AD.
Calsenilin regulates presenilin 1/γ‐secretase‐mediated N‐cadherin ∊‐cleavage and β‐catenin signaling
Jang, Changhwan,Choi, Jin‐,Kyu,Na, Yeo‐,Jung,Jang, Byungki,Wasco, Wilma,Buxbaum, Joseph D.,Kim, Yong‐,Sun,Choi, Eun‐,Kyoung Federation of American Society for Experimental Bi 2011 The FASEB Journal Vol.25 No.12
<P>Presenilin 1 (PS1) is a component of the γ-secretase complex that cleaves a variety of type I membrane proteins, including the β-amyloid precursor protein (β-APP), Notch, and neuronal (N)- and epithelial (E)-cadherins. N-cadherin is an essential adhesion molecule that forms a complex with, and is cleaved by, PS1/γ-secretase and β-catenin in the plasma membrane. The purpose of this study was to determine whether calsenilin, a presenilin-interacting protein, has a functional role in PS1/γ-secretase-mediated N-cadherin ε-cleavage using Western blot analysis, RT-PCR, immunoprecipitation, subcellular fractionation, biotinylation, and a luciferase reporter assay in SH-SY5Y neuroblastoma cells. Here, we demonstrate that the expression of calsenilin leads to a disruption of PS1/γ-secretase-mediated ε-cleavage of N-cadherin, which results in the significant accumulation of N-cadherin C-terminal fragment 1 (Ncad/CTF1), the reduction of cytoplasmic Ncad/CTF2 release, and a deceleration of PS1-CTF delivery to the cell surface. Interestingly, we also found that the expression of calsenilin is associated with the redistribution of β-catenin from the cell surface to a cytoplasmic pool, as well as with the negative regulation of genes that are targets of T-cell factor/β-catenin nuclear signaling. Taken together, our findings suggest that calsenilin is a novel negative regulator of N-cadherin processing that plays an important role in β-catenin signaling.</P>
Calsenilin, a Presenilin Interactor, Regulates RhoA Signaling and Neurite Outgrowth
Kim, Hee-Jun,Lee, Won-Haeng,Kim, Mo-Jong,Shin, Sunmee,Jang, Byungki,Park, Jae-Bong,Wasco, Wilma,Buxbaum, Joseph D.,Kim, Yong-Sun,Choi, Eun-Kyoung MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.4
<P>Calsenilin modulates A-type potassium channels, regulates presenilin-mediated γ-secretase activity, and represses prodynorphin and <I>c-fos</I> genes expression. RhoA is involved in various cellular functions including proliferation, differentiation, migration, transcription, and regulation of the actin cytoskeleton. Although recent studies demonstrate that calsenilin can directly interact with RhoA and that RhoA inactivation is essential for neuritogenesis, it is uncertain whether there is a link between calsenilin and RhoA-regulated neuritogenesis. Here, we investigated the role of calsenilin in RhoA-regulated neuritogenesis using in vitro and in vivo systems. We found that calsenilin induced RhoA inactivation, which accompanied RhoA phosphorylation and the reduced phosphorylation levels of LIM kinase (LIMK) and cofilin. Interestingly, PC12 cells overexpressing either full-length (FL) or the caspase 3-derived C-terminal fragment (CTF) of calsenilin significantly inactivated RhoA through its interaction with RhoA and p190 Rho GTPase-activating protein (p190RhoGAP). In addition, cells expressing FL and the CTF of calsenilin had increased neurite outgrowth compared to cells expressing the N-terminal fragment (NTF) of calsenilin or vector alone. Moreover, Tat-C3 and Y27632 treatment significantly increased the percentage of neurite-bearing cells, neurite length, and the number of neurites in cells. Finally, calsenilin deficiency in the brains of calsenilin-knockout mice significantly interfered with RhoA inactivation. These findings suggest that calsenilin contributes to neuritogenesis through RhoA inactivation.</P>
Phosphorylation of calsenilin at Ser63 regulates its cleavage by caspase-3
Choi, Eun-Kyoung,Miller, J.S.,Zaidi, N.F.,Salih, E.,Buxbaum, J.D.,Wasco, W. 한림대학교 환경·생명과학연구소 2003 [일송 국제심포지엄] 노화와 만성퇴행성 신경질환 Vol.- No.5
Calsenilin is a member of the neuronal calcium sensor(NCS) family of proteins that interacts with the presenilins. Casenilin has been found to act as a Kv4α channel interactor and as a transcriptional repressor. We have recently shown that calsenilin can be cleaved by caspase-3 and that its cleavage separates the conserved calcium-binding domain from the variable N-terminal domain. Here we demonstrate that calsenilin can be phosphorylated by casein kinase I and that its phosphorylation can be regulated by intracellular calcium. In addition, phosphorylate calsenilin is a substrate for serine/threonine protein phosphatase(PP) 1 and/or 2A. Phosphorylation within the N-terminal domain at Ser63, the major phosphorylation site of calsenilin, inhibits cleavage of the molecule by caspase-3. Given that the N-terminal domain of calsenilin is not conserved in the larger NCS family including other KChIP/CALP proteins, phosphorylation of calsenilin may regulate a functional role that is unique to this member of the superfamily