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| First Name: | Jack T. | | Last Name: | Rogers | | Title: | Director of Neurochemistry Laboratory, MGH/Associate Professor (HMS) | | Advanced Degrees: | Ph.D. | | Affiliation: | Massachusetts General Hospital/Harvard University | | Department: | Psychiatry-Neuroscience | | Street Address 1: | CNY2 | | Street Address 2: | 149, 13 Street | | City: | Charlestown | | State/Province: | MA | | Zip/Postal Code: | 02129 | Country/Territory: | U.S.A. | | Phone: | 1-617-726-8838 | | Email Address: |  |
Disclosure:
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Member reports the following financial or other potential conflicts of interest: [Last Modified: 23 September 2010]
Iron metabolism and the discovery that the Alzheimer's Amyloid precursor protein (APP) is an iron regulated ferroxidase.
Translational control of the APP mRNA and other neurodegenerative disease mRNA by iron and inflammatory signaling
RNA directed therapeutics to treat Alzheimer's disease and Parkinson's disease
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View all comments by Jack T. Rogers
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Aging Process, Prion Diseases, Parkinson Disease, Alzheimer Disease
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Bioinformatics/Statistics, A-beta PP/A-beta, Molecular and Cell biology, Signal transduction, Oxidative Stress
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The greatest gap to be filed is to find exactly how closely iron metabolism is central to the function of the amyloid precursor protein (APP) and thus ALzheimer's disease. There is also the central link that several neurodegenerative disease gene mRNA are regulated via unexpectedly similar iron dependent pathways |
Our Neurochemistry laboratory at MGH contributed greatly to the novel finding that the Alzheimer’s precursor protein (APP) incorporates a dual role in iron metabolism (see Duce et al.,Cell 2010). First, APP displays Ferroxidase activity, which detoxifies deleterious Fe2+ into the storage form of iron as Fe3+. Second, it shows APP has a clear role in iron export, where APP is in association with the well-known iron export protein, ferroportin also associated with hemachomatosis. Thus APP helps ferroportin to export iron and detoxify neurons from potential iron accelerated oxidative stress. This is the culmination of a highly productive collaboration between the Oxidation Biology Group lead by Dr. Ashley Bush (Melbourne) and the Neurochemistry laboratory of Dr. Jack Rogers (Psych-Neuroscience, MGH at Harvard).
It had long been suspected that APP expression and function is regulated by iron and iron metabolism. This paper finally pinpoints this function, attributable to a “tell-tale” iron binding REXXE site (at residues 401-417 in the E2 domain of APP-770), confirmed to be an iron oxidase site in the APP protein itself (see U. S. Patent WO/2002/034766, Rogers et al 2002). Also there is a uniquely configured Iron-responsive Element (IRE) RNA stem loop in the 5’untranslated region of the APP transcript (Rogers et al, 2002, J. Biol. Chem. 277, 45518–45528). IRE stem loops on mRNAs, can be viewed as a genetic tag linking the particular protein expressed to iron metabolism.
This key APP-ferroxidase paper is now complemented by a recent contribution to J. Biol. Chem. (Cho/Cahill et al., 2010, in press) from Jack's Neurochemistry laboratory that elegantly defines how iron metabolism controls APP expression. Here Cho/Cahill et al (2010) demonstrated that Iron-regulatory Protein-1 (IRP1), an RNA binding protein that controls iron homeostasis closely, also controls iron dependent expression of APP. IRP1 and IRP2 have long been known to co-regulate the iron storage protein ferritin mRNAs and the transferrin receptor mRNA stability in all cells of the body. These new findings are consistent with the ferroxidase activity of APP and now lay the foundation for future studies to determine exactly how APP interfaces with iron metabolism.
We expect, that using these new insights, new therapies will be developed to prevent neurotoxic iron accumulation during the course of AD and other devastating neurodegenerative disease, particularly in mini strokes of Alzheimer’s disease.
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That the expression of APP, alpha-synuclein and SOD-1 and can be limited at the level of message translation via their unexpectedly linked 5'untranslated regions to provide a therapeutic impact for AD, PD and ALS. |
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