Bess Frost, PhD

Associate Professor
Bartell Zachry Distinguished Professor for Research in Neurodegenerative Disorders

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
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.

Lab Members

https://www.bessfrostlab.com/

Publications

1.	Ramirez, P., Zuniga, G., Sun, W., Beckmann, A., Ochoa, E., DeVos, S. L., Hyman, B., Chiu, G., Roy, E. R., Cao, W., Orr, M., Buggia-Prevot, V., Ray, W. J., & Frost, B. (2022). Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system. Progress in neurobiology, 208, 102181. https://doi.org/10.1016/j.pneurobio.2021.102181
2.	Mahoney, R., Ochoa Thomas, E., Ramirez, P., Miller, H. E., Beckmann, A., Zuniga, G., Dobrowolski, R., & Frost, B. (2020). Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium. Cell reports, 32(2), 107900. https://doi.org/10.1016/j.celrep.2020.107900
3.	Ochoa Thomas, E., Zuniga, G., Sun, W., & Frost, B. (2020). Awakening the dark side: retrotransposon activation in neurodegenerative disorders. Current opinion in neurobiology, 61, 65–72. https://doi.org/10.1016/j.conb.2020.01.012
4.	Sun, W., Samimi, H., Gamez, M., Zare, H., & Frost, B. (2018). Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nature neuroscience, 21(8), 1038–1048. https://doi.org/10.1038/s41593-018-0194-1
5.	Orr, M. E., Sullivan, A. C., & Frost, B. (2017). A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies. Trends in pharmacological sciences, 38(7), 637–648. https://doi.org/10.1016/j.tips.2017.03.011
6.	Sun, W., Yan, C., Frost, B., Wang, X., Hou, C., Zeng, M., Gao, H., Kang, Y., & Liu, J. (2016). Pomegranate extract decreases oxidative stress and alleviates mitochondrial impairment by activating AMPK-Nrf2 in hypothalamic paraventricular nucleus of spontaneously hypertensive rats. Scientific reports, 6, 34246. https://doi.org/10.1038/srep34246
7.	Frost, B. (2016). Alzheimer's disease: An acquired neurodegenerative laminopathy. Nucleus (Austin, Tex.), 7(3), 275–283. https://doi.org/10.1080/19491034.2016.1183859
8.	Frost, B., Bardai, F. H., & Feany, M. B. (2016). Lamin Dysfunction Mediates Neurodegeneration in Tauopathies. Current biology : CB, 26(1), 129–136. https://doi.org/10.1016/j.cub.2015.11.039
9.	Frost, B., Götz, J., & Feany, M. B. (2015). Connecting the dots between tau dysfunction and neurodegeneration. Trends in cell biology, 25(1), 46–53. https://doi.org/10.1016/j.tcb.2014.07.005
10.	Merlo, P., Frost, B., Peng, S., Yang, Y. J., Park, P. J., & Feany, M. (2014). p53 prevents neurodegeneration by regulating synaptic genes. Proceedings of the National Academy of Sciences of the United States of America, 111(50), 18055–18060. https://doi.org/10.1073/pnas.1419083111
11.	Frost, B., Hemberg, M., Lewis, J., & Feany, M. B. (2014). Tau promotes neurodegeneration through global chromatin relaxation. Nature neuroscience, 17(3), 357–366. https://doi.org/10.1038/nn.3639
12.	Frost, B., & Diamond, M. I. (2010). Prion-like mechanisms in neurodegenerative diseases. Nature reviews. Neuroscience, 11(3), 155–159. https://doi.org/10.1038/nrn2786
13.	Frost, B., & Diamond, M. I. (2009). The expanding realm of prion phenomena in neurodegenerative disease. Prion, 3(2), 74–77. https://doi.org/10.4161/pri.3.2.8754
14.	Frost, B., Jacks, R. L., & Diamond, M. I. (2009). Propagation of tau misfolding from the outside to the inside of a cell. The Journal of biological chemistry, 284(19), 12845–12852. https://doi.org/10.1074/jbc.M808759200
15.	Frost, B., Ollesch, J., Wille, H., & Diamond, M. I. (2009). Conformational diversity of wild-type Tau fibrils specified by templated conformation change. The Journal of biological chemistry, 284(6), 3546–3551. https://doi.org/10.1074/jbc.M805627200

https://scholars.uthscsa.edu/en/persons/susan-e-frost