Contact

Location: Office: Barshop Institute 1055

Department

Cell Systems and Anatomy

Bess Frost, PhD

Assistant Professor

Personal Statement:

My research interest revolves around the basic neurobiology mediating brain aging and neurodegeneration. Thus far in my academic career, I have pioneered work that ignited a now prominent area of research, which is that tau, a key pathological player in Alzheimer’s disease and other tauopathies, adopts prion-like characteristics that help explain its pathological spread through the brain and the diverse disease phenotypes of the human tauopathies (Frost, Jacks et al. 2009, Frost, Ollesch et al. 2009). In addition, using Drosophila and mouse models of tauopathy, bioinformatic approaches, post-mortem human brain tissue, and advanced microscopy, I have identified disruption of nuclear architecture (Frost, Bardai et al. 2015) and subsequent widespread relaxation of heterochromatic DNA (Frost, Hemberg et al. 2014) as a novel mechanism whereby tau causes neuronal death in tauopathies, including human Alzheimer’s disease.

My laboratory currently studies fundamental processes in cell biology that drive tau-induced neuronal death. 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 analyses in postmortem human tissue. We have recently reported that decondensation of heterochromatin causes transposable element activation in neurodegenerative tauopathy, a process that we find is amenable to both genetic and pharmacological suppression (Sun, Samimi et al. 2018). We have also found that tau-induced involution of the nuclear envelope contributes to neurotoxicity through aberrant RNA export (Cornelison, Levy et. al. 2018).


Education

Year Degree Discipline Institution
2004 BS Cellular and Molecular Biology The University of Texas at Austin
Austin, TX
2009 PhD Biomedical Sciences University of California San Francisco
San Francisco, CA
Postdoctoral Fellowship Department of Pathology Brigham and Women`s Hospital/Harvard Medical School
Boston , MA

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.

Awards & Accomplishments

Awards

Year Award
2019 Presidential Excellence Award for Junior Research Scholar, UTHSA
This award goes to one junior faculty member who has demonstrated exemplary performance in research

Grants

Project #: 1 R01 AG062475-01A1
Period: 07/01/19 – 06/30/24
Funding Agency: NIA/NINDS
Title: Regulation of neuronal clearance pathways via nuclear calcium signaling in Alzheimer’s disease
Status: Pending, scored within funding line
Role: Co-Investigator, PI: Radek Dobrowolski
% Effort: 25
Total Direct Costs to Frost: $631,360.00
Grant Detail: The goal of the proposed project is to determine the mechanism whereby Presenilin 1 and tau regulate nuclear calcium and the extent to which deficits in nuclear calcium contribute to neurodegeneration.
Project #: 1 RF1 NS112391-01 (R01 equivalent)
Period: 07/01/19 – 06/30/24
Funding Agency: NIA/NINDS
Title: Investigating the role of transposable element dysregulation as a driver of neurotoxicity in tauopathy
Status: Active
Role: Principal Investigator
% Effort: 25
Total Direct Costs: $1,250,000.00
Grant Detail: The goal of the proposed project is to understand how transposable element activation induces neurotoxicity, to extend our studies to mouse models of tauopathy, and to determine the extent of transposable element activation and mobilization in human tauopathy.
Project #: P30 AG013319-25S2
Period: 07/01/19 – 06/30/20
Funding Agency: NIA
Title: ADRD Administrative Supplement
Status: Active
Role: Co-Investigator, PI’s on P30: Dr. Randy Strong and Peter Hornsby
% Effort: 5
Total Direct Costs on Supplement: $249,433.00
Grant Detail: The goal of this proposal is to determine whether compounds identified as lifespan or healthspan-extending through the Interventions Testing Program effectively suppress neurodegeneration in tau transgenic mice and Drosophila.
Project #: 1 R01 AG057896
Period: 02/15/19 – 11/30/23
Funding Agency: NIA/NINDS
Title: Mechanisms of tau- and aging-induced neurological dysfunction: Focus on the nucleus
Status: Active
Role: Principal Investigator
% Effort: 25
Total Direct Costs: $1,329,223.00
Grant Detail: The goal of the proposed project is to identify repercussions of nuclear disruption in tauopathy and aging with a focus on RNA export.
Project #: N/A
Period: 09/01/19 – 08/31/20
Funding Agency: UTHSCSA Pepper Center
Title: Evaluating the extent of transposable element activation in brain and fluid from patients with Alzheimer’s disease
Status: Active
Role: Principal Investigator
% Effort: 8.3
Total Costs: $25,000.00
Grant Detail: This project utilizes single-nucleus retrotransposon capture sequencing from control and human Alzheimer’s disease brain tissue at mid- and late-stage disease to determine if transposable elements actively mobilize in the context of human Alzheimer’s disease.

Publications

Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium.
Rebekah Mahoney, Elizabeth Ochoa Thomas, Paulino Ramirez, Henry E Miller, Adrian Beckmann, Gabrielle Zuniga, Radek Dobrowolski, Bess Frost
Cell Reports. 2020 Jul 14;32(2):107900. doi: 10.1016/j.celrep.2020.107900.

Awakening the dark side: retrotransposon activation in neurodegenerative disorders.
Elizabeth Ochoa Thomas, Gabbe Zuniga, Wenyan Sun, Bess Frost
Current Opinion in Neurobiology. 2020 Apr;61:65-72. doi: 10.1016/j.conb.2020.01.012.
PMCID: PMC7198348 (available on 2021-04-01)

Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies.
Wenyan Sun, Hanie Samimi, Maria Gamez, Habil Zare, Bess Frost
Nature Neuroscience. 2018 Aug;21(8):1038-1048. doi: 10.1038/s41593-018-0194-1. Epub 2018 Jul 23.
PMCID: PMC6095477

A brief overview of tauopathy: Causes, consequences and therapeutic strategies.
Miranda E Orr, A Campbell Sullivan, Bess Frost
Trends in Pharmacological Sciences. 2017 Jul;38(7):637-648. doi: 10.1016/j.tips.2017.03.011. Epub 2017 Apr 25.
PMCID: PMC5476494

Pomegranate extract decreases oxidative stress and alleviates mitochondrial impairment by activating AMPK-Nrf2 in hypothalamic paraventricular nucleus of spontaneously hypertensive rats.
Wenyan Sun, Chunhong Yan, Bess Frost, Xin Wang, Chen Hou, Mengqi Zeng, Hongli Gao, Yuming Kang, Jiankang Liu
Scientific Reports. 2016 Oct 7;6:34246. doi: 10.1038/srep34246.
PMCID: PMC5054377

Alzheimer’s disease: An acquired neurodegenerative laminopathy.
Bess Frost
Nucleus. 2016 May 3;7(3):275-83. doi: 10.1080/19491034.2016.1183859. Epub 2016 May 11.
PMCID: PMC4991240

Lamin Dysfunction Mediates Neurodegeneration in Tauopathies.
Bess Frost, Farah H Bardai, Mel B Feany
Current Biology. 2016 Jan 11;26(1):129-36. doi: 10.1016/j.cub.2015.11.039. Epub 2015 Dec 24.
PMCID: PMC4713335

Connecting the dots between tau dysfunction and neurodegeneration.
Bess Frost, Jürgen Götz, Mel B Feany
Trends in Cell Biology. 2015 Jan;25(1):46-53. doi: 10.1016/j.tcb.2014.07.005. Epub 2014 Aug 26.
PMCID: PMC4275400

p53 prevents neurodegeneration by regulating synaptic genes.
Paola Merlo, Bess Frost, Shouyong Peng, Yawei J Yang, Peter J Park, Mel Feany
PNAS. 2014 Dec 16;111(50):18055-60. doi: 10.1073/pnas.1419083111. Epub 2014 Dec 1.
PMCID: PMC4273405

Tau promotes neurodegeneration through global chromatin relaxation.
Bess Frost, Martin Hemberg, Jada Lewis, Mel B Feany
Nature Neuroscience. 2014 Mar;17(3):357-66. doi: 10.1038/nn.3639. Epub 2014 Jan 26.
PMCID: PMC4012297
(See also accompanying News and Views in same issue.)

Prion-like mechanisms in neurodegenerative diseases.
Bess Frost, Marc I Diamond
Nature Reviews Neuroscience. 2010 Mar;11(3):155-9. doi: 10.1038/nrn2786. Epub 2009 Dec 23.
PMCID: PMC3648341

The expanding realm of prion phenomena in neurodegenerative disease.
Bess Frost, Marc I Diamond
Prion. 2009 Apr-Jun;3(2):74-7. Epub 2009 Apr 16.
PMCID: PMC2712602

Propagation of tau misfolding from the outside to the inside of a cell.
Bess Frost, Rachel L Jacks, Marc I Diamond
J Biol Chem. 2009 May 8;284(19):12845-52. doi: 10.1074/jbc.M808759200. Epub 2009 Mar 11.
PMCID: PMC2676015

Conformational diversity of wild-type Tau fibrils specified by templated conformation change.
Bess Frost, Julian Ollesch, Holger Wille, Marc I Diamond
J Biol Chem. 2009 Feb 6;284(6):3546-51. doi: 10.1074/jbc.M805627200. Epub 2008 Nov 14
PMCID: PMC2635036