Director: Russell L. Margolis, M.D.
Co-Director: Dobrila Rudnicki, Ph.D.
Link to PubMed publication for Rudnicki DD
The Laboratory of Genetic Neurobiology currently focuses on four interrelated projects:
- Exploration of the genetic etiology and pathogenesis of psychiatric disorders, especially schizophrenia, using a candidate-gene approach. We have detected families in which mutations in the genes DISC1 and NPAS3 segregate with schizophrenia (Sachs, 2005). Through the use of cell models, including iPS cells generated from family members (Chiang, 2011), animals models, and molecular and biochemical approaches, we propose to determine the relationship of the newly discovered mutations to normal gene function and pathways potentially involved in disease pathogenesis. We remain interested in using novel approaches to find additional risk factors for major mental illness (Bruce, 2009), including a microchip array that we designed to detect repeat length variations within the human genome.
- The therapeutic implications of endogenous regulation of the Huntington’s disease (HD) gene expression. We have recently demonstrated that a transcript antisense to the HD gene serves to regulate expression of the HD gene (Chung, 2011). Current investigations involve exploring the interrelationship among the antisense transcript, the HD gene, and the HD expansion mutation. The goal 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.
- Investigation of the pathogenesis of Huntington's disease like-2 (HDL2), another disorder clinically (Margolis et al, 2001) and genetically (Holmes, 2001) characterized in our laboratory. HDL2 is clinically indistinguishable from HD but is caused by a CTG expansion in an alternatively spliced exon of the gene junctophilin-3. Current research is focused on developing cell and animal models of HDL2 pathogenesis, and further defining the clinical, genetic, and epidemiological characteristics of the disease in humans (Rudnicki, 2007; Rudnicki, 2008; Seixas, in press). The guiding hypothesis is that comparison of HDL2 with HD will lead to the discovery of convergent modes of pathogensis central to both diseases.
- The role of RNA toxicity in neurodegeneration. Recent work in our lab has demonstrated that transcripts containing long stretches of CAG or CUG repeats have neurotoxic properties (Rudnicki, 2007). We are using cell and animal models and molecular techniques to explore how this toxicity relates to the pathogenensis of HD and HDL2, and potentially other neurodegenerative diseases.
Russell L. Margolis, M.D.
Dobrila D. Rudnicki, Ph.D.
Xin Sun, Ph.D.
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, 2001.
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.
Bruce HA, Sachs NA, Rudnicki DD, Lin SG, Willour VL, Cowell JK, Conroy J, McQuaid D, Rossi M, Gaile DP, Nowak NJ, Holmes SE, Sklar P, Ross CA, DeLisi LE, Margolis RL. Long tandem repeats as a form of genomic copy number variation: structure and length polymorphism of a chromosome 5p repeat in control and schizophrenia populations. Psychiatric Genetics, 19 ( class="src1"2009):64-71.
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.
Chiang C-H, Su Y, Wen Z, Yoritomo N, Ross CA, Margolis RL (co-corresponding author), Song H, Ming G-l. Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation. Molecular Psychiatry 16 (2011):358-60.
Work on all of these projects is performed in close collaboration with Dr. Christopher Ross, Dr. Fred Nucifora, and Dr. Misha Pletnikov within the Division of Neurobiology and Drs. Troncoso and Pletnikova in the Department of Pathology.