Liebman Lab

Susan W. Liebman, PhD

Research Professor

Email: sliebman@unr.edu
Phone: (775) 782-7338
Fax: (775) 784-1620

Howard Medical Sciences 151
1664 North Virginia Street, Mail Stop 0318
Reno, NV 89557-0318

Appointments

Education

  • B.A. 1968 Massachusetts Institute of Technology, Cambridge, MA
  • M.S. 1969 Harvard University, Cambridge, MA
  • Ph.D. 1974 University of Rochester, Rochester, NY

Publications

View PubMed Publications

Research Interests

Certain neurodegenerative diseases, such as ‘mad cow' disease, are transmitted in an unusual way-- so unusual that it challenges the central dogma. Indeed, the infectious agent for these diseases appears to be the PrP protein without any nucleic acid. Infectivity depends upon the shape into which the PrP protein is folded: when some PrP is in its disease-causing (‘prion') conformation, it converts normal PrP into that form too. In addition, prion-like aggregates of Abeta, α-synuclein, TDP-43, and huntingtin are respectively associated with Alzheimer's (AD), Parkinson's, amyotrophic lateral sclerosis (ALS)/ frontotemporal dementia (FTD) and Huntington's diseases.

Curiously, several genetic traits in yeast are propagated by this unusual ‘protein only' mechanism, and the term prion has been expanded to include them. We have studied yeast prions extensively to elucidate the factors that influence prion appearance and inheritance and to identify new prions. We are now using our expertise with yeast prions to focus on the genesis and toxicity of human prion-like disease aggregates. Results obtained in yeast will then be tested in flies, primary cortical neurons and mice, by collaborators.

We previously established that individual yeast prions can form self-seeding aggregates with more than one conformation ("variants or strains") associated with distinct properties. Prion variants self-propagate by attracting their soluble isoforms to join them and adopt their variant-specific structure. Likewise, PrP, Abeta, α-synuclein, huntingtin, tau and TDP-43 have each been reported to form distinct aggregate phenotypes that are associated with different disease characteristics. We are now using yeast to isolate and characterize variants of TDP-43. This will definitively demonstrate the existence of heritableTDP-43 variants and will open the door to the study of patient variants in yeast, thereby facilitating development of variant specific treatments.

Proteins encoded by genes that cause familial neurodegenerative disease often form insoluble amyloid-like aggregates in diseased patients' neurons. Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Findings by others that deletion of the ATXN2 ortholog, PBP1, reduced yeast TDP-43 toxicity, lead to discoveries that ATXN2 is an amyotrophic lateral sclerosis (ALS) risk factor and that lowered ATXN2 levels are therapeutic in a mouse ALS model. Likewise, new yeast neurodegenerative disease models could allow identification of disease risk factors and provide a drug discovery platform. 

Mutations in SS18L1, which encodes the calcium-responsive transactivator (CREST), are associated with ALS. CREST, a chromatin-remodeling factor, contains an aggregation prone domain. We found that CREST is toxic in yeast and inhibits silencing of telomerically located genes. Toxicity is enhanced by the [PIN+] prion and reduced by deletion of PBP1/ATXN2. CREST forms nuclear and occasionally cytoplasmic foci that stain with an amyloid dye, thioflavin T. Overexpression of PBP1 caused considerable CREST co-localization with PBP1 tagged cytoplasmic granules, which might promote toxic aggregation of CREST. These results extend the spectrum of ALS associated proteins affected by PBP1/ATXN2, supporting the hypothesis that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.

As previous modifier screens were not exhaustive we have now identified several new modifier genes that we are exploring. We are also using two new approaches to identify toxicity modifiers: 1) transposon mutagenesis and deep sequencing to quickly identify all genes that become essential in the presence of the human disease proteins and 2) direct selection against aggregation (yTRAP) to uncover additional modifier loci, as well as intragenic dominant mutations that reduce toxicity. We are also starting similar modifier screens on CREST.

Another focus of the lab is to determine how TDP-43 is associated with toxicity. Several studies find that TDP-43 alters mitochondrial function. We have found that TDP-43 is much more toxic when yeast is grown in non-fermentable media requiring respiration than when grown on fermentable carbon sources. However, we also found that TDP-43 remains toxic in the absence of respiration. Thus, there is a TDP-43 toxicity target in yeast distinct from respiration and respiration is not required for this toxicity. One possibility is that the free radical oxygen species produced by respiration activate TDP-43 to become more toxic or make TDP-43 targets more vulnerable. Indeed, we found that hydrogen peroxide increases the toxicity of TDP-43.

Our data further show that TDP-43 inhibits autophagy in yeast and that when the toxicity of TDP-43 is altered, either by intragenic mutations or extra-genic modifiers, the reduction in autophagy associated with TDP-43 expression parallels its effects on toxicity. This supports the hypothesis that a major component of TDP-43’s effect on toxicity arises from its effect on autophagy. The findings further indicate that the mechanism by which TDP-43 inhibits autophagy involves reducing the frequency with which the autophagy inhibitor TORC1 enters TOROID structures, where TORC can no longer function. Since the structure of yeast TORC1 has been reported to be very similar to its mammalian counterpart, a similar mechanism may occur in higher organisms. Thus drugs that prevent TDP-43 from inhibiting TOROID fromation may prove therapeutic for a variety of neurodegenerative diseases characterized byTDP-43 aggregation.

 

Contact Dr. Liebman (sliebman@unr.edu) directly if you are interested in joining Liebman laboratory

 

Current Laboratory Members

Dr. Sei-Kyoung Park, PhD

2006- Research Assistant Professor 
Graduate work, Department of Microbiology, Iowa State University with Dr. Gregory J. Phillips
Postdoc, Cell Biology and Metabolism Branch, NICHD/NIH, with Catherine Jackson

Sangeun Park, MS

2016- Research Associate
BS and MS in Department of Microbiology from Seoul Women's University,
Research Associate 2008-15, Department of Microbiology, Immunology and Molecular Genetics, U. of California, Los Angeles
Research Associate 2003-7, Department of Chemical Genomics in Korea Research Institute of Chemical Technology

Irina Derkatch, PhD

2021-Research Associate Professor

Alumni

Former Postdoctoral Fellows 

  • Yury Chernoff, PhD, Professor of Biological Sciences, Georgia Tech
  • Zhijian Qian, PhD, Associate Professor of Medicine, University of Illinois Chicago
  • Anita L. Manogaran, PhD, Assistant Professor, Biological Sciences, Marquette University
  • Basant K. Patel, Associate Professor of Biotechnology, Indian Institute of Technology Hyderabad, India
  • Vibha Taneja, Associate Professor, Department of Research, Sir Ganga Ram Hospital

Former PhD Students

  • Slav Bagriantsev, PhD, Associate Professor of Cellular and Molecular Physiology, Yale School of Medicine
  • Karen Downs, PhD, Professor of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin Madison
  • Richard Anthony, PhD, Associate Professor of Biology & Biomedical Engineering, Rose-Hulman Institute of Technology, Indiana
  • Paul Sutton, PhD, MD, FACP, Associate Professor Medicine, Adjunct Associate Professor Biomedical Informatics and Medical Education, University of Washington
  • Vidhu Mathur, PhD, Scientist, Annexon Biosciences
  • Rong Lui, PhD, Medical Writing Lead, EMD Serono, Inc.
  • Hanhua Huang, PhD, Director of Biology Avidity Biosciences, La Jolla, CA
  • Michael Bradley, PhD, Staff Scientist Ecolab, Nalco

Former Lab Managers

  • Joo Y. Hong, BS, Research Specialist, 1997-2017, Currently Lab Manager for Dr. Evan Stubbs, Jr.
  • Sherrie Masse, MS, Research Specialist 1998-2000, Currently Director Regulatory Affairs, Global Regulatory Lead at AbbVie
  • Margaret Cavenagh, MS Research Specialist 1978-1982, Currently Program Specialist at the National Cancer Institute, NIH
  • Gary P. Newnam, BS, Research Specialist 1993-1997, Currently Research Technician in Yury Chernoff Lab