Abstract
The central nervous system deposition by neurons and glia of beta A4 amyloid protein is an important contributing factor to the development of Alzheimer's disease. Amyloidogenic cells overexpress amyloid precursor protein (APP) mRNAs suggesting a transcriptional or post-transcriptional defect may contribute to this process. We have previously shown that APP mRNAs display regulated stability which is dependent on a 29-base element within the 3'-untranslated region (UTR). This domain specifically interacted with several cytoplasmic RNA-binding proteins. We have purified these APP RNA-binding proteins from a human T-cell leukemia and demonstrate that five cytoplasmic proteins of 70, 48, 47, 39, and 38 kDa form the previously observed APP RNA protein complexes. Amino acid sequence analyses showed that the 70-, 48-, and 47-kDa proteins were fragments of nucleolin and that the 39- and 38-kDa proteins were heterogeneous nuclear ribonucleoprotein (hnRNP) C protein. Northwestern and Western blot analyses of purified material further confirmed these data. Nucleolin protein is known to shuttle between the nucleus and cytoplasm but hnRNP C has not been reported within the cytoplasm. This report of sequence specific, mRNA binding by nucleolin and hnRNP C suggests that these proteins participate in the post-transcriptional regulation of APP mRNA through 3'-UTR, site-specific interactions.
Highlights
Alzheimer's disease (AD)l is characterized by the presence of f)A4 amyloid protein deposits in neuritic plaques found in the brains of affected individuals. (3A4 amyloid protein is derived from the proteolytic cleavage of (3 amyloid precursor proteins (APP) encoded by a single copy gene located on chromosome 21 [1]
Mitogen-driven entry into the cell cycle has been associated with substantial changes in mRNA decay rates [7, 8]
We have previously shown that APP mRNAs decay in resting human peripheral blood mononuclear cells (PBMC) with a half-life of 4 h [12]
Summary
Alzheimer's disease (AD)l is characterized by the presence of f)A4 amyloid protein deposits in neuritic (senile) plaques found in the brains of affected individuals. (3A4 amyloid protein is derived from the proteolytic cleavage of (3 amyloid precursor proteins (APP) encoded by a single copy gene located on chromosome 21 [1]. Transformed cells grown in vitro with exogenous Recent reports of amyloid deposition in the brain of APP transgenic mice [4] further strengthens the connection between overexpression of Increased APP mRNA levels have been observed in central nervous system neurons of AD patients [5]. As mRNA and protein levels are often correlated, the overexpression of APP mRNAs may be an important predisposing factor to Increased APP gene transcription and/or decreased APP mRNA degradation could account for increased steady state levels. Mitogen-driven entry into the cell cycle has been associated with substantial changes in mRNA decay rates [7, 8]
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