title: Calsenilin is degraded by the ubiquitin-proteasome pathway.
abstract: Calsenilin, a neuronal calcium binding protein that has been shown to have multiple functions in the cell, interacts with presenilin 1 (PS1) and presenilin 2 (PS2), represses gene transcription and binds to A-type voltage-gated potassium channels. In addition, increased levels of calsenilin are observed in the brains of Alzheimer's disease and epilepsy patients. The present study was designed to investigate the molecular mechanism of calsenilin degradation pathways in cultured cells. Here, we demonstrate that inhibition of the ubiquitin-proteasomal pathway (UPP) but not lysosomal pathway markedly increased the expression levels of calsenilin. Immunofluorescence analysis revealed that following proteasomal inhibition calsenilin accumulated in the endoplasmic reticulum (ER) and Golgi, while lysosomal inhibition had no effect on calsenilin localization. In addition, we found the change of subcellular localization of PS1 from diffuse pattern to punctuate staining pattern in the ER and perinuclear region in the presence of calsenilin. These findings suggest that calsenilin degradation is primarily mediated by the UPP and that impairment in the UPP may contribute to the involvement of calsenilin in disease-associated neurodegeneration.
authors.affiliation: Ilsong Institute of Life Science, Hallym University, Anyang, Republic of Korea.
authors.forename: Changhwan
authors.initials: C
authors.lastname: Jang
authors.forename: Jin-Kyu
authors.initials: JK
authors.lastname: Choi
authors.forename: EunYoung
authors.initials: E
authors.lastname: Kim
authors.forename: Eun-Su
authors.initials: ES
authors.lastname: Park
authors.forename: Wilma
authors.initials: W
authors.lastname: Wasco
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Choi
mesh_terms: D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D012097:Repressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D015853:Cysteine Proteinase Inhibitors; C496749:KCNIP3 protein, human; D051605:Kv Channel-Interacting Proteins; D007976:Leupeptins; D061988:Proteasome Inhibitors; D012097:Repressor Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde