James S. Malter

 

 

Post-Transcriptional Gene Regulation of Amyloid Precursor Protein mRNA

E-mail: jsmalter@wisc.edu

Research Strengths: Molecular Neuroscience, Neurobiology of Disease

We are interested in how amyloid precursor protein (APP) mRNA is regulated at the molecular level. APP is over-produced in Alzheimer's Disease (AD) and much evidence implicates Beta-amyloid, a 39-42 amino acid peptide cleaved from APP as the pathogenic entity in AD. Excess APP production can be caused by excess APP mRNA accumulation. Indeed, in multiple studies of AD or Down's Syndrome patients, APP mRNA levels are often elevated. In the case of Down's Syndrome, the extra APP gene inherited by these individuals likely accounts for their excess APP mRNA levels. In AD patients, however, it remains unclear how APP mRNA levels are regulated. We have shown that stabilization of APP mRNA could account for its accumulation in AD brain. Working from this hypothesis, we have characterized the decay of APP mRNA in resting and activated cells, as well as cycling tumor cells of neuronal lineage. The decay rate depends on the interplay between 2 regulatory domains located in the 3' untranslated region. One region functions to prevent mRNA decay while the other promotes decay. In addition, we have shown that distinct RNA binding proteins specifically interact with both regulatory elements. We are currently cloning the RNA binding proteins which interact with the stabilizing element as well as pursuing an antisense strategy to nullify its function and decrease steady state APP mRNA levels. Finally, we anticipate the creation of a knock-in mouse which lacks the regulatory elements as an in vivo model to study APP mRNA decay. We utilize a wide mix of standard cell and molecular biology methods, protein biochemistry, and molecular genetics.

Selected Publications:

• Broytman, O. and J.S. Malter. 2004. A beta: The good, the bad, and the unforeseen. J. Neurosci Res. 75: 301-306.
• Todd, P.K., J.S. Malter, and J.S. Mack. 2003. Whisker stimulation-dependent translation of FMRP in the barrel cortex requires activation of type I metabotropic glutamate receptors. Brain Res. 110: 267-78. [PDF]
• Todd, P.K., K.J. Mack, and J.S. Malter. 2003. The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95. Proc. Natl. Acad. Sci. 100: 14374-14378.
• Todd, P.K. and J.S. Malter. 2002. Fragile X mental retardation protein in plasticity and disease. J. Neuro. Res. 70: 623-630. [PDF]
• Westmark, C. and J.S. Malter. 2001. Up-regulation of nucleolin mRNA and protein in peripheral blood mononuclear cells by extracellular-regulated kinase. J. Biol. Chem. 276: 1119-1126. [PDF]
• Rajagopolan, L. and J.S. Malter. 2000. Growth factor mediated stabilization of amyloid precursor protein mRNA is mediated by a conserved 29-nucleotide sequence in the 3'-untranslated region. J. Neurochem. 74: 52-59. [PDF]
• Rajagopalan, L.E., C.J. Westmark, J.A. Jarzembowski, and J.S. Malter. 1998. hnRNP C increases amyloid precursor protein (APP) production by stabilizing APP mRNA. Nucleic Acids Res. 26: 3418-3423. [PDF]