Harvard Catalyst Profiles

Trinity College, Dublin	BA	1977	Genetics
University of Pennsylvania, Philadelphia	MSC	1979	Genetics
St Mary's Hosp. Imperial College London)	Ph.D.	1884	Biochemistry
MIT, Cambridge, MA	Post doc	1987	Molecular Biology

Over the past two decades, Jack Rogers, PhD, has been a leader in conducting research with his colleagues in the Neurochemistry laboratory in the Dept. of Psychiatry-Neuroscience at MGH. They have transformed the way seemingly separate neurodegenerative diseases are now viewed, revealing underlying common mechanisms at the gene level. In doing so, Dr. Rogers and colleagues were the first scientists to identify a common therapeutic target—the iron response element—on several of the genes that code for proteins implicated in neurodegeneration. These findings may successfully target the gene that encodes the amyloid precursor protein (APP) implicated in Alzheimer’s disease, and the gene that encodes the protein alpha-synuclein in Parkinson’s disease. To advance these findings, the Neurochemistry Lab is moving forward from these basic mechanisms to the study of molecules that can reach the iron response element—the common therapeutic target—and act to inhibit the production of the disease-causing proteins. This research is now in the in vivo testing stage using mouse models of the diseases and beginning on human clinical trials (Nigel Greig, NIA).

Our Neurochemistry Laboratory at the Dept. of Psychiatry-Neuroscience at MGH is co-run by our colleagues Dr. Catherine Cahill and Dr. Xudong Huang, Of recent, in close collaboration with Dr. Catherine Cahill, my scientific focus has been the translational regulation of the mRNAs for the Amyloid Precursor Protein (APP) and the L- and subunits of the iron storage protein, ferritin relevant to Anemia and Alzheimer's Disease (AD). Our central question is - how do RNA structures and their cognate RNA binding proteins control APP-mRNA and ferritin mRNA translation relevant to neurodegenerative diseases?

Over time, we showed that APP mRNA was interacts with the Iron-regulatory Proteins, IRP-1 and IRP-2, which control intracellular iron homeostasis (Rogers et al., (2002) J.Biol. Chem, 277: 45518-28). Since then we reported in top journals that this regulatory pattern placed the amyloid precursor protein (APP) in the family of iron genes. Secreted APP(s) exhibits intrinsic copper-dependent activity to change the Fe2+ /Fe3+ balance suggesting that the cytoprotective role of APP(s) operates via iron homeostasis. We reported that Poly (C)-binding Proteins interact with the 5'untranslated region (5'UTR) of ferritin mRNAs in addition to IRP-1 and IRP-2. These events contribute to a new model of intracellular iron homeostasis. Poly [C]-binding proteins appear to be important where IRP-1/IRP-2 were previously thought to be the sole players to control intracellular ferritin and APP levels, as relevant to AD and Parkinson’s Disease.

Our lab have conducted three collaborative high throughput screens with the Broad Institute to identify small molecules to limit APP, alpha-synuclein and prion protein translation in a therapeutic mode in the pipeline to limit neurodegenerative diseases, of most recent this is being progressed in the case of Parkinson's Disease . Originally we screened 110,000 LDDN compounds to identify small RNA-binding drugs that suppress APP-mRNA translation via the APP 5'UTR stem loop (Laboratory for Drug Development in Neurodegeneration (LDDN: Dr. Ross Stein and Dr. Marcie Glicksman , co-Directors). These APP 5’UTR leads will be developed into new therapeutic agents that inhibit Ab-peptide and amyloid plaque build-up, but also provide critical probes to understand how IRP-1/IRP-2 control APP mRNA translation.

Dr. Rogers has directed research projects for undergraduates from Harvard College, Dartmouth College, Scripps College and the University of Pennsylvania as well as a recent accelerated science student, Mr. Sanjan Sarang in Houston as part of their school systems excellence in science program. Our own students support equity and inclusion and I taught Mr. Nabeil Sarhan, Ms Amanda Venti , Mr. Soon Hyook Lee , Mr. Jared Courtney , Ms Caitlin Philips. as well as Ms Sandra Payton who worked as my primary technician and has since graduated in optometry School. Dr. Sanghamitra Bandyopadhyay was the first Postdoctoral Fellow and is presently on the faculty in the Institute of toxicology in Lucknow, India. I mentored Dr. Andrew Thomson over several publications with Dr. Peter Leedman at the University of Perth (Au) and am the external examiner for their Ph.D candidates. We have most enjoyed collaborating with Prof Debomoy Lahiri (Univ. Indiana), Dr. Ashely Bush and Dr. Scott Ayton (Univ. of Melbourne), Dr. Vivek Venkataramani (Univ. of Gottingen) and Dr. Michael Lardelli (Univ. of Adelaide, Australia) and Dr Ann Smith (Univ. of Missouri, Kansas City).

• Iron homeostasis
• Neurodegenerative Disease
• RNA therapeutics