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Barshop Institute for Longevity and Aging Studies

Bess Frost, Ph.D.

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Bess Frost, Ph.D.

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Assistant Professor
Department of Cellular & Structural Biology
Barshop Institute for Longevity and Aging Studies
UT Health Science Center at San Antonio
210-567-1000

RESEARCH

The Frost laboratory studies fundamental processes in cell biology that drive neurodegeneration. We employ a multi-system approach to rapidly identify, test, and validate hypotheses that are relevant to human disease. Early discovery takes place in Drosophila, a model organism that is well suited for investigating issues of causality in disease processes. To determine if our studies are relevant to human disease, we complement Drosophila work with comparative analyses in postmortem human brain.

A major focus of the laboratory is on tauopathy. Tauopathies, including Alzheimer’s disease, are pathologically characterized by the deposition of neurofibrillary tangles composed of tau protein in the brains of affected individuals. Motivated by our previous identification of widespread relaxation of heterochromatic DNA as a novel disease mechanism in tauopathies, we are currently pursuing the following areas of study:

Role of the lamin nucleoskeleton in tauopathies

The filamentous meshwork formed by the lamin nucleoskeleton provides a scaffold for the anchoring of highly condensed heterochromatic DNA to the inner nuclear envelope, thereby maintaining the three-dimensional architecture of the genome. Insight into the importance of lamins to cellular viability can be gleaned from the laminopathies, severe disorders caused by mutations in genes encoding lamins. Clinical features of laminopathies include accelerated aging or “progeroid” syndromes, alongside cellular abnormalities such as misshapen nuclei and loss of heterochromatin organization. Our current studies suggest that lamin misregulation though aberrant cytoskeletal-nucleoskeletal coupling drives heterochromatin relaxation in tauopathies. This work identifies the lamin nucleoskeleton as a molecular link between aging, the single most important risk factor for developing common neurodegenerative diseases, and basic mechanisms of cellular senescence.

Involvement of noncoding RNAs in tauopathies

Chromosomal regions in close proximity to telomeres and centromeres are packaged into tightly wound DNA termed “constitutive heterochromatin,” which is rich in transposable element sequences. PIWI-interacting RNAs (piRNAs) are a highly abundant class of small noncoding RNAs that silence transposable element expression. While piRNAs have been implicated in establishing long-term memory, the role of piRNAs in the brain remains largely unexplored. We are currently interested in piRNA and transposable element misregulation as a consequence of heterochromatin relaxation in tauopathies.

Recent Publications

  1. Frost B, Bardai FH, Feany MB (2015) Lamin Dysfunction Mediates Neurodegeneration in Taupathies. Current Biology, In Press
  2. Frost B, Gotz J, Feany M (2015) Connecting the dots between tau dysfunction and neurodegeneration. Trends in Cell Biology, 25(1):46-53. PMCID: PMC4275400.
  3. Merlo P, Frost B, Peng S, Yang Y, Park P, Feany M (2014) p53 prevents neurodegeneration by regulating synaptic genes. PNAS, 111(50):18055-60. PMCID: PMC4273405.
  4. Frost B, Hemberg M, Lewis J, Feany M (2014) Tau promotes neurodegeneration through global chromatin relaxation. Nature Neuroscience, 17(3):357-66. PMCID: PMC4012297. (See also accompanying News and Views in same issue.)
  5. Frost B, Diamond MI (2010) Prion-like mechanisms in neurodegenerative diseases. Nature Reviews Neuroscience, 11(3)155-9. PMCID: PMC3648341.
  6. Frost B, Diamond MI (2009) The expanding realm of prion phenomena in neurodegenerative disease. Prion, 3(2)74-7. PMCID: PMC2712602.
  7. Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem., 284(19):12845-52. PMCID: PMC2676015.
  8. Frost B, Ollesch J, Wille H, Diamond MI (2009) Conformational diversity of wild-type Tau fibrils specified by templated conformation change. J Biol Chem., 284(6):3546-51. PMCID: PMC2635036.

 
 
   
 
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The Sam and Ann Barshop Institute for Longevity and Aging Studies

15355 Lambda Drive
San Antonio, Texas  78245
P: 210-562-6140 F: 210-562-6110
Contact: barshopinstitute@uthscsa.edu
Updated: 6/22/2011
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