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Russell L. Margolis, MD

Department Affiliations Division of Neurobiology, Department of Psychiatry
Rank Professor; Clinical Director JH Schizophrenia Center; Director Laboratory of Genetic Neurobiology
Office Phone 410-614-4262 or 410-955-1536
Lab Phone
Fax 443-927-7695
SOM Address 8-121 CMSC

Rachael Cohen 2013

Research Interests

The Laboratory of Genetic Neurobiology focuses on the etiology and pathogenesis of diseases that fall at the intersection of neurology, psychiatry, and genetics. Among these diseases are a group of relatively rare Mendelian disorders, such as Huntington’s disease (HD)and the spinocerebellar ataxias, that are characterized pathologically by degeneration of specific neuronal populations and clinically by motor, psychiatric, and cognitive abnormalities. These diseases follow a relentless course to death or severe disability. Our fundamental hypothesis is that understanding the etiology and pathogenesis of these disorders will facilitate the development of rational therapeutics for them, and may provide clues to the etiology of more common and etiologically complex neuropsychiatric disorders, such as Alzheimer’s disease, Parkinson’s disease, bipolar affective disorder, schizophrenia, and autism.

As one test of this hypothesis, we are exploring the molecular features of the HD locus. For instance,we recently found an antisense transcript expressed from the HD locus; one function of this transcript is to negatively regulate expression of the HD gene. Much effort has gone into developing oligonucleotides or siRNA strategies to suppress expression of the mutant HD allele, but these efforts face a number of challenges (sufficient delivery to the brain, target specificity). We have proposed an alternative therapeutic strategy, upregulation of the HD antisense transcript by small molecules (e.g., potential drugs). Assays are currently underdevelopment to test this strategy.

In keeping with this overall hypothesis, we have applied conventional and novel genetic methods to find the etiology of two previously undescribed Mendelian neurodegenerative disorders. Each is caused by a repeat expansion mutation. In one, the causative repeat expansion mutation appears to increase expression of a brain-specific regulatory unit of phosphatase PP2A, potentially leading to abnormal patterns of phosphorylation. In the other, the repeat expansion leads to expression of a toxic RNA transcript and loss of expression of a junctional protein with potential consequences for calcium flux. We are investigating both disorders with a combination of molecular, cellular, and animal models, including transcriptome and proteome analyses and iPS cells from patients.

We are now also applying some of the lessons learned from Mendelian disorders to more complex disorders, and especially schizophrenia. We have detected families with rare mutations in two genes, DISC1 (involved in neuronal migration, synaptic generation, and synaptic plasticity) and NPAS3 (transcription factor regulating hippocampal development), each of which has been previously associated with schizophrenia. We are developing cell, animal, and biochemical models,including human iPS cells, to explore the implications of these mutations.

Students in the laboratory will have the opportunity to attend clinics and observe the diagnosis and treatment of patients with Huntington’s disease, schizophrenia, and other neuropsychiatric disorders. Students may also participate in field trips undertaken to ascertain and characterize families with one of these diseases.


Research Profile

  • 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.
  • 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.
  • Sachs NA, Sawa A, Holmes SE, Ross CA, DeLisi LE, Margolis RL. A frameshift mutation in Disrupted in Schizophrenia 1 segregates with schizophrenia and schizoaffective disorder in an American family. Molecular Psychiatry 10(2005) 758-64
  • 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, 2011, Human Molecular Genetics, (2011):3467-77.
  • Seixas AI, Holmes SE, Takeshima H, Pavlovich A, Sachs N, Pruitt JL, Silveira I, Ross CA, Margolis RL, Rudnicki DD. Loss of junctophilin-3 contributes to Huntington’s Disease-like 2 pathogenesis, Annals of Neurology, 71(2012):245-257.
  • Yu L, Arbez N, Nucifora LG, Sells G, DeLisi L, Ross CA, Margolis RL, Nucifora FC. A mutation in NPAS3 segregates with mental Illness. Molecular Psychiatry (2013), in press.