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Neurochemistry is the study of fundamental genetic mechanisms in the human body that regulate how chemicals govern the activity of nerve cells. The failure of these mechanisms can lead to the onset of devastating life-threatening and chronic diseases, foremost among them: Alzheimer’s disease, Parkinson’s disease, amyotrophic laterals sclerosis (ALS), autism, schizophrenia and major depression.
A second critical area of neurochemistry research is how cell signaling through molecules called cytokines regulate processes in the brain and in other organs. Cytokine dysregulation has been implicated in many diseases of the developing intestine and brain during gestation.
Over the past decade and more, Jack Rogers, PhD, has been a leader in conducting research that has transformed the way seemingly separate neurodegenerative diseases are now viewed, revealing underlying common mechanisms at the genetic 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, Dr. Rogers 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.
Positive results in these tests will enable progression to clinical trials and, hopefully, to the development of drugs with impact across the neurodegenerative disease spectrum. The idea is to develop blockers of the genes that produce the “culprit” proteins at the pass before they can cause nerve damage. Other possible clinical benefits of this research relate to the potential of dietary interventions to protect against this neuro-degeneration.
The Iron Response Element: A Common Neurodegenerative Disease Therapeutic Target
The common iron-responsive element motif in the 5’untranslated regions of the Alzheimer’s associated, amyloid precursor protein (APP), Parkinson’s associated, alpha Synuclein, transmissible spongiform encephalopathies (TSEs) associated Prion protein and now reporting on the amyotrophic lateral sclerosis ALS associated transcript, C9orf72, offers a novel approach to targeting multiple neurodegenerative diseases.
The laboratory has screened multiple drug libraries containing thousands of both FDA approved as well as other novel small molecule drugs and nutraceuticals. One of these, JTR-009 is a small molecule whose mechanism is to modulate the binding of the IRP-1 RNA binding protein to the Iron Response Element stem loop. JTR-009 clamps onto the IRE and blocks the translation of the Alzheimer’s associated Amyloid precursor protein (figure below). Other novel small molecules, including BL-1 have been screened to target IREs associated with Parkinson’s disease and Prion disease and are currently under investigation, requiring testing in animal models and ultimately final testing in human clinical trials.
- Jack Rogers, PhD
Director, Laboratory of Neurochemistry
Program Director, Associate Professor of Psychiatry-Neuroscience, Harvard Medical School
- Dr. Xudong Huang
Assistant Professor of Psychiatry Neuroscience, Harvard Medical School
- Catherine Cahill, PhD
Assistant Professor of Psychiatry-Neuroscience, Harvard Medical School
- The 5’-Untranslated Regions of the C9orf72 mRNA Exhibits a Phylogenetic Alignment to the Cis-aconitase Iron-responsive Element; Novel Therapies for Amyotrophic Lateral Sclerosis. Neuroscience and Medicine
- Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1, Journal of Biological Chemistry
- Novel 5′ Untranslated Region Directed Blockers of Iron-Regulatory Protein-1 Dependent Amyloid Precursor Protein Translation: Implications for Down Syndrome and Alzheimer's Disease, PLoS ONE
- Interleukin (IL) 1beta induction of IL-6 is mediated by a novel phosphatidylinositol 3-kinase-dependent AKT/IkappaB kinase alpha pathway targeting activator protein-1, Journal of Biological Chemistry
- Iron-Export Ferroxidase Activity of β-Amyloid Precursor Protein Is Inhibited by Zinc in Alzheimer's Disease, Cell
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