Director: Russell L. Margolis, M.D.
The goal of investigations directed by Dr. Margolis is to improve the understanding and treatment of neuropsychiatric disorders, leveraging insights from monogenic disorders such as Huntington’s disease to approach complex disorders, particularly schizophrenia. The work can be divided into three parts:
- Laboratory of Genetic Neurobiology
- Ultra-high field strength 7T MRI and schizophrenia
- Conceptualization, diagnosis, and treatment of schizophrenia
Laboratory of Genetic Neurobiology
Exploration of the etiology and pathogenesis of monogenic neuropsychiatric disorders characterized by neurodegeneration and repeat expansion mutation.
- Pan P. Li, Ph.D
- Hongxuan Feng, Ph.D.
- Qi Sun, M.S.
- Tiana Sepahpour, MBE
Regulation of the expression of the Huntington’s disease (HD) gene, huntingtin (HTT)
HD is an autosomal dominant, adult onset, neurodegenerative disorder caused by an expansion of a CAG repeat in exon of HTT. There is no treatment, and the disease progresses to death 15-20 years after onset. We have demonstrated that, under certain circumstances, a transcript antisense to HTT (HTT-AS) serves to regulate expression of HTT. Current investigations involve exploring the interrelationship among HTT-AS, HTT, and the HD expansion mutation. One goal, in collaboration with the NIH National Center for Advancing Translation Sciences (NCATS), is to determine if the antisense transcript can be upregulated, perhaps by small molecules, and thereby used as an endogenous knockdown strategy to decrease expression of the toxic HD mutation (see figure below). A related goal is to improve understanding of the mechanisms by which HTT expression is regulated.
Chung DW, Rudnicki DD, Yu L, Margolis RL. A natural antisense transcript at the Huntington’s disease repeat locus regulates HTT expression. Human Molecular Genetics, 20 (2011):3467-..77.
Khaled et al, High-throughput screening to identify small molecules that suppress huntingtin promoter activity or activate huntingtin-antisense promoter activity, in review.
Pathogenesis of Huntington's disease like-2 (HDL2)
Our laboratory discovered and characterized HDL2, an autosomal dominant neurodegenerative disorder that is clinically, genetically, and pathologically remarkably similar to HD. HDL2 is caused by a CTG/CAG repeat expansion in an alternatively spliced exon of the gene junctophilin-3 (JPH3); pathogenesis appears to derive from a combination of loss-of-function of JPH3, RNA-mediated toxicity, and polyglutamine toxicity from a protein encoded by a cryptic antisense transcript. Current bench research is focused on using human brain tissue, iPSCs and other cell models, and transgenic, knockout, and knock-in mouse models to test each of these mechanisms. Projects include the electrophysiological impact of the HDL2 mutation, the role of somatic expansion in pathogenesis, the extent and reversibility of antisense-mediated neurotoxicity, the effect of the mutation on mitochondrial function, the composition of HDL2 intranuclear aggregates, and the proteomic and transcriptomic impact of the HDL2 mutation compared to the HD mutation. The guiding hypothesis is that comparison of HDL2 with HD will lead to the discovery of convergent modes of pathogenesis central to both diseases, and new therapeutic targets.
In addition, we continue to work with collaborators in South Africa to develop additional understanding of the clinical, genetic, and neuroanatomic manifestations of HDL2.
Holmes SE, O’Hearn E, Callahan C, Hwang HS, Rosenblatt A, Ingersoll-Ashworth RG, Fleisher A, Stevanin G, Brice A, Potter NT, Ross CA, Margolis RL. A CTG trinucleotide repeat expansion in Junctophilin 3 is associated with Huntington's Disease-Like 2 (HDL2). Nature Genetics, 29 (2001): 377-378.
Rudnicki DD, Holmes SE, Lin M, Thorton CA, Ross CA, Margolis RL. Huntington’s disease-like 2 is associated with CUG repeat containing RNA foci. Annals of Neurology, 61 (2007):272-82.
Rudnicki DD, Pletnikova O, Vansattel JP, Ross CA, Margolis RL. A comparison of Huntington’s disease and Huntington’s disease-like 2 neuropathology. Journal of Neuropathology and Experimental Neurology, 67(2008):366-74.
Seixas AI, Holmes SE, Takeshima H, Pavlovich A, Sachs N, Pruitt JL, Silveira I, Ross CA, Margolis RL (co-corresponding author), Rudnicki DD. Loss of junctophilin-3 contributes to Huntington’s Disease-like 2 pathogenesis, Annals of Neurology, 71(2012):245-257
Anderson DG, Haagensen M, Ferreira-Correia A, Pierson R, Carr J, Krause A, Margolis RL. Emerging differences between Huntington's disease-like 2 and Huntington's disease: A comparison using MRI brain volumetry. Neuroimage Clin. 2019; 21:101666
Anderson DG, Ferreira-Correia A, Rodrigues FB, Aziz NA, Carr J, Wild EJ, Kaurse A, Margolis RL. Comparison of the Huntington’s disease-like 2 and Huntington’s disease clinical phenotypes. Move Dis Clin Pract, 2019, Mar 12;6(4):302-311.
Spinocerebellar ataxia type 12 (SCA12)
Our laboratory discovered and characterized SCA12, a late onset neurodegenerative disorder characterized clinically by tremor, gait disturbance, cognitive and psychiatric manifestations. SCA12 is caused by a repeat expansion in the gene PPP2R2B, which encodes multiple protein isoforms that function as regulatory subunits of the phosphatase PP2A. We hypothesize that the repeat expansion alters the normal expression of these protein subunits, leading to abnormalities in the phosphoproteome and subsequent neurotoxicity. Led by Dr. Pan Li, our group is testing this hypothesis, as well as alternative hypotheses, using human iPSCs and mouse models generated with a novel application of CRISPR/Cas9, developed by Dr. Li, that facilitates seamless insertions or deletions of targeted genomic loci.
Holmes SE, O'Hearn E, McInnis MG, Kwak NG, Gorelick-Feldman DA, Kleiderlein JK, Callahan C, Sherr M, Sharp AH, Sumner AJ, Ashworth RG, Ananth U, Seltzer W, Vieria-Saecker AM, Epplen JT, Reiss O, Ross CA, Margolis RL. Expansion of a novel CAG trinucleotide repeat in the 5' region of PPP2R2B is associated with SCA12, Nature Genetics, 23 (1999): 391-392.
O’Hearn EE, Hwang HS, Holmes SE, Rudnicki DD, Chung DW, Seixas AI, Cohen RL, Ross CA, Trojanowski, JQ, Pletnikova O, Troncoso JC, Margolis RL. Neuropathology and cellular pathogenesis of spinocerebellar ataxia type 12. Mov Disord. 30(2015):1813-24.
Li P and Margolis RL. Use of single guided Cas9 nickase to facilitate precise and efficient genome editing in human iPSCs, in review.
Ultra-high field strength 7T MRI and schizophrenia
Diagnosis, nosology, and pathophysiology. In conjunction with Dr. Jun Hua, Peter van Zijl, and their colleagues at the Kirby Center for Functional Brain Imaging, the lab is using the Kirby Center‘s powerful 7 Tesla scanner to examine anatomical, neurochemical, and functional abnormalities in schizophrenia, based in part on investigations were initially developed in studies of Huntington’s disease. Areas of active investigation include resting state thalamo-cortical connectivity, and vascular volume as assessed by iVASO, a method for determining brain arteriolar volume developed by Dr. Hua and colleagues. Future projects included using ultra-high field strength fMRI to validate a novel nosological scheme for psychotic disorders (in collaboration with Dr. Godfrey Pearlson), functional connectivity at the resolution of individual cortical layers (in collaboration with Dr. Tilak Ratnanather), and functional connectivity as a predictor of treatment response in schizophrenia.
Brandt AS, Unschuld PG, Pradhan S, Lim IA, Churchill G, Harris AD, Hua J, Barker PB, Ross CA, van Zijl PC, Edden RA, Margolis RL. Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A (1)H MRS Study at 7Tesla. Schizophr Res. 2016 Apr;172(1-3):101-5
Hua J, Brandt AS, Lee S, Blair NI, Wu Y, Lui S, Patel J, Faria AV, Lim IA, Unschuld PG, Pekar JJ, van Zijl PC, Ross CA, Margolis RL. Abnormal Grey Matter Arteriolar Cerebral Blood Volume in Schizophrenia Measured With 3D Inflow-Based Vascular-Space-Occupancy MRI at 7T. Schizophr Bull. 43(2017):620-632
Hua J, Blair NIS, Paez A, Choe A, Barber AD, Brandt A, Lim IAL, Xu F, Kamath V, Pekar JJ, van Zijl PCM, Ross CA, Margolis RL. Altered functional connectivity between sub-regions in the thalamus and cortex in schizophrenia patients measured by resting state BOLD fMRI at 7T. Schizophr Res. 2019 Apr;206:370-377.
Conceptualization, diagnosis, and treatment of schizophrenia
Challenges in the conception and diagnosis of schizophrenia
Dr. Margolis, as senior psychiatrist of one of the two Johns Hopkins Bayview Early Psychosis Clinics, has been working closely with Krista Baker, LCPC and Max Wolcott, MSW to determine the extent to which other disorders, including anxiety and affective disorders, are misdiagnosed as schizophrenia, and the reasons for this error. On going studies are investigating the impact of consultations offered by the clinic on long term clinical outcome, and use of a new rating scale to evaluate the progress of inpatients with psychotic disorders. In conjunction with Dr. Ross, Dr. Margolis has examined the impact of current NIMH policy on schizophrenia research in light of underlying conceptions about the nature of schizophrenia and other serious mental illnesses.
CA, Margolis RL. Research Domain Criteria: Strengths, weaknesses, and potential alternatives for future psychiatric research. Molecular Neuropsychiatry, 2019 Oct;5(4):218-236.
Ross CA, Margolis RL. Research Domain Criteria: Cutting Edge Neuroscience or Galen’s Humors Revisited. Molec Neuropsychiatr, 2018 Dec;4(3):158-163.
Coulter C, Baker K, Margolis RL. Specialized consultation for suspected recent-onset schizophrenia: diagnostic clarity and the distorting impact of anxiety and reported auditory hallucinations. J Psychiatr Prac, 2019 Mar;25(2):76-81.
Improvement in clinical care to patients with recent onset psychosis
The two Johns Hopkins Bayview Early Psychosis Intervention Clinics have joined a consortium of all clinics providing specialized care for patients with recent onset psychosis in Maryland and Pennsylvania, funded by the NIMH. The consortium, known as Connect Learning Health System, will collect extensive longitudinal data on ~ 500 patients. The data will be used to formulate and answer a series of research questions related to improvement in clinical practice, and will be available for use in a variety of research studies. Dr. Margolis and Ms. Baker serve on the Executive Committee of the consortium.
- Christopher A. Ross, M.D., Ph.D.
- Jun Hua, Ph.D.
- Peter van Zijl, Ph.D.
- Wanzhen Duan, M.D., Ph.D.
- Xia Feng, Ph.D.
- Juan Troncoso, M.D.
- Frederick Nucifora, DO, PhD
- Leslie Nucifora, Ph.D.
- Tilak Ratnanther, Ph.D.
- Krista Baker, LCPC
- Max Wolcott, MSW
- Adrian Paez, B.A.
- Xinyuan Miao, Ph.D.
- Kia Ultz, M.S.
- ShanShan Zhu, Ph.D.
- Stefan Strack, Ph.D. (Univ of Iowa)
- Xiping Zhan, Ph.D. (Howard University)
- David Anderson, MB BcH, Ph.D. (Univ of Witwatersand)
- Amanda Krause, MB BcH, Ph.D. (Univ of Witwatersand)
- Mark Henderson, Ph.D. (NCATS, NIH)
- Vanessa Wheeler, Ph.D. (Harvard Univ/MGH)
- Godfrey Pearlson, MBBS (Institute for Living/Univ of Connecticut)
- Melanie Bennett, Ph.D. (Univ of Maryland)