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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.
See Dr. Rogers’ publications.
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.
On The Cover: The image shows a predictive consensus tertiary RNA structure for the human APP IRE based on the two secondary structures reported. The image was generated by Sohan Mikkilineni, MIT. For details see the article by Cho et al., J. Biological Chemistry.
The laboratory has screened multiple drug libraries containing thousands of both FDA approved as well as other novel small molecule drugs and neutraceuticals. 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.
Dr. Roger’s and colleagues review in Neuroscience and Medicine:
The 5’-Untranslated Regions of the C9orf72 mRNA Exhibits a Phylogenetic Alignment to the Cis-aconitase Iron-responsive Element; Novel Therapies for Amytrophic Lateral Sclerosis
Jack Rogers, PhD Director, Laboratory of Neurochemistry Program Director, Associate Professor of Psychiatry-Neuroscience, Harvard Medical School
Dr. Rogers received his PhD from St. Mary’s Hospital, University College London and conducted postdoctoral research at MIT.
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Dr. Xudong HuangCo-director of NeurochemistryAssistant Professor of Psychiatry Neuroscience, Harvard Medical School
Dr. Huang received his PhD in chemistry from MIT and completed his postdoctoral training at the Neuroscience Center at Mass General. His major research activities and achievements are centered upon:
Dr. Huang and Dr. Rogers have launched a CNS drug discovery initiative and are identifying potential sponsors to commercialize recent invention on amyloid precursor protein (APP) mRNA blockers for treating Down’s syndrome and Alzheimer’s disease (AD). Dr. Huang has identified and characterized the role of environmental stressors such as metal oxide nanoparticles in neuronal cell death using high content imaging technology, contemplating their potential link to neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, given that nano-neurotoxicity is a very sensitive issue among both the scientific community and the public. Additionally, both independent component analysis (ICA)- and ant colony optimization-based algorithms have been applied to Alzheimer-related DNA microarray data analysis and gene order computation, respectively, for Alzheimer-associated gene expression clustering and potential biomarker identification. Dr. Huang and his colleagues have developed an automatic ICA-based method coupled with Support Vector Machine (SVM) classifier that can differentiate AD and mild cognitive impairment (MCI) patients from age-matched healthy control subjects, using clinical MRI data. In addition, Dr. Huang has supervised four undergraduate, graduate and medical students, three technicians, and nine postdoctoral fellows over the years.
Catherine Cahill, PhDPrincipal Investigator, Laboratory of Neurochemistry Assistant Professor of Psychiatry-Neuroscience, Harvard Medical School
Dr. Cahill received her PhD from University College Dublin, Ireland and did her postdoctoral research in the Department of Immunology at the Babraham Research Institute, Cambridge, UK, and at Dana-Farber Cancer Institute and Harvard Medical School.
Her major research interests include:
The biochemical signaling pathways between the gastrointestinal tract and the central nervous system, referred to as the “gut-brain axis” is a bi-directional communication system which can be impaired in many neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Down syndrome (DS). Systemic inflammation due to infection can play a major role. Dr. Cahill has discovered novel biochemical pathways involving the inflammation associated transcription factors, activator protein 1 (AP-1) and nuclear factor kappa B (NFkB) in the human intestine leading to increases in pro-inflammatory cytokines. These studies have revealed therapeutic targets which may ultimately lead to therapies to accelerate delayed intestinal development in the premature infant and which are also relevant to inflammation and colon cancer.
Under her direction, the Neurochemistry Lab’s research portfolio has expanded to include the study of neurodevelopmental disorders including Down syndrome and her most recent research aims to understand the impact of early life stressors and environmental exposures, including lead, on the developing brain where neurodegenerative mechanisms may be at work earlier in life. Inflammation prior to birth, triggered by maternal infection, toxins or bad nutrition, including iron deficiency, may be an underlying mechanism. In collaboration with Dr. Rogers and Stanford University scientist Ahmad Salehi, PhD, Dr. Cahill proposes to test the potential of novel small molecule JTR-009 to treat Alzheimer’s disease associated Down syndrome (AD-DS). Down syndrome is associated with several abnormalities, including intellectual disability and early onset AD. Triplication of chromosome 21, containing the AD-associated amyloid precursor protein (APP) gene in DS means increased amyloid burden for these patients. The aim is to modulate APP in early fetal development in a mouse model of DS and moving from “bench to bedside,” to identify periods when the administration of therapeutic molecules such as JTR-009 would have a protective effect.
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Susruthi Rajanala is a student in the 7-year BA/MD program at Boston University and began medical school in the fall of 2016. Her interests include neurodegenerative diseases and DNA/RNA based therapies. She assists with western blots and cell assays as well as manuscript drafting and editing for the lab.
Conan Huang received his BS in chemical engineering from Brown University in May 2014. He is a medical student at NYU School of Medicine. In the Neurochemistry Laboratory, he contributed to the studies of the novel small molecule inhibitors of neurodegenerative disease genes including those for the potential treatment of Alzheimer’s disease
Bosco Tam is a medical student in the University of Hong Kong under the program of Bachelor of Medicine and Bachelor of Surgery Program (MBBS) a 6-year curriculum (2012-2018). “In the summer of 2012, I was very lucky to be accepted into Dr. Roger’s and Dr. Cahill’s laboratory in Massachusetts General Hospital to learn and help with their research on neurodegeneration and inflammation. It was a wonderful and stimulating experience and provided me a glimpse into one of the best medical research institutes in the world”.
Publications by Dr. Rogers
Publications by Dr. Cahill
Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1
Novel 5′ Untranslated Region Directed Blockers of Iron-Regulatory Protein-1 Dependent Amyloid Precursor Protein Translation: Implications for Down Syndrome and Alzheimer's Disease
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
Iron-Export Ferroxidase Activity of β-Amyloid Precursor Protein Is Inhibited by Zinc in Alzheimer's Disease
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Contact either Dr. Jack Rogers, 617-726-8838 or Dr. Catherine Cahill, 617-643-4029 if you would like to inquire about philanthrophic contributions to help support this research.
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