A phosphorylated, carboxy-terminal fragment of β-amyloid precursor protein localizes to the splicing factor compartment

Zoia Muresan, Virgil Muresan

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

β-Amyloid precursor protein (APP) is implicated in the pathobiology of Alzheimer's disease (AD). To gain insight into its function, we have investigated the proteolytic processing and post-translational modification of APP in relation to its intracellular traffic and localization. The proteolytic processing that generates the amyloid β-peptide (Aβ) also releases into the cytoplasm the carboxy-terminal fragment of APP, Cγ. Using the catecholaminergic cell line, CAD, and an antibody to a form of APP that is phosphorylated at Thr668 (pAPP; numbering for APP695), we show that a phosphorylated, carboxy-terminal fragment of APP, probably Cγ, is present in the nucleus, where it localizes to subnuclear particles. The labeling with anti-pAPP antibody co-localizes with proteins that define the splicing factor compartment (SFC) [e.g. the small nuclear ribonucleoprotein (snRNP), U2B, and serine/arginine-rich (SR) proteins], but is excluded from the coiled bodies and the gems. This distribution of pAPP epitopes was found in CAD cells independent of their state of differentiation, as well as in primary cortical neurons, epithelial cells and fibroblasts. We further show that exogenously expressed Cγ becomes phosphorylated, and distributes throughout the cell. A fraction of this Cγ is translocated into the nucleus, where it co-localizes with endogenous pAPP epitopes. Finally, we show that the APP binding, scaffolding protein, Fe65 co-localizes with pAPP epitopes and with expressed Cγ at intranuclear speckles. These results suggest that phosphorylated Cγ accumulates at the SFC. Thus, APP may play a role in pre-mRNA splicing, and Fe65 and APP phosphorylation may regulate this function.

Original languageEnglish (US)
Pages (from-to)475-488
Number of pages14
JournalHuman molecular genetics
Volume13
Issue number5
DOIs
StatePublished - Mar 1 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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