NIHBC 05 BG RM 324
5 MEMORIAL DR
BETHESDA MD 20892
Dr. Frakes earned her B.S. from John Carroll University and Ph.D. from the Ohio State University. During her Ph.D. in Brian Kaspar’s laboratory, she studied the cell non-autonomous mechanisms by which astrocytes and microglia induce motor neuron death in the fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS). While studying this neurodegenerative disease, she became fascinated how the brain can cope with misfolded, disease-causing proteins for decades only to succumb to disease upon aging. This led her to join Andrew Dillin’s laboratory at UC Berkeley where she discovered that a subset of astrocyte-like glial cells plays a central role in regulating protein homeostasis and longevity in C. elegans. In November 2021, she joined NIDDK with a co-appointment in NINDS. The Frakes Lab uses combination of model organisms and tools to investigate how glial cells sense and respond to cellular stress which the goal of identifying the mechanisms that drive aging and disease.
As gatekeepers and guardians of the nervous system, glia act as first responders to disruptions in homeostasis long before patients or neurologists are aware of disease. Therefore, investigating the mechanisms by which glia sense and respond to cellular stressors (such as excess/insufficient nutrients or misfolded proteins) offers a unique opportunity to identify therapeutic targets and biomarkers for disease. In our lab, we leverage the versatility of multiple model systems (C. elegans, cell culture, and mice) to reveal the mechanisms glial cells employ to sense and respond to cellular stressors to coordinate homeostasis within the central nervous system and peripheral tissues. We use a combination of tools including genetics, microscopy, animal behavioral assays, viral transduction, and single-cell functional genomics. Our long-term goal is to identify the fundamental cellular mechanisms that drive aging and give rise to age-onset metabolic and neurodegenerative diseases.
- Frakes AE, Metcalf MG, Tronnes SU, Bar-Ziv R, Durieux J, Gildea HK, Kandahari N, Monshietehadi S, Dillin A. Four glial cells regulate ER stress resistance and longevity via neuropeptide signaling in C. elegans. Science. 2020 Jan 24;367(6476):436-440. PMID: 31974253. Perspective in Science by Miklas JM and Brunet A. PMID: 31974234
- Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, Bevan A, Foust KD, Godbout JP, Popovich PG, Guttridge DC, Kaspar BK. Microglia Induce Motor Neuron Death via the Classical NF-κB Pathway in Amyotrophic Lateral Sclerosis. Neuron. 2014 Mar 5;81(5):1009-23. PMID: 24607225.
- Frakes AE, Braun L, Ferraiuolo L, Guttridge DC, Kaspar BK. Additive amelioration of ALS by co-targeting independent pathogenic mechanisms. Annals of Clinical and Translational Neurology, 2017 Feb;4(2):76-86. PubMed PMID: 28168207;
- Bar-Ziv Z*, Frakes AE*, Higuchi-Sanabria R*, Bolas T, Frankino PA, Gildea HK, Metcalf MG, Dillin A. Measurements of physiological stress responses in C. elegans. J. Vis. Exp. (159), e61001, doi:10.3791/61001 (2020). *co-first authors
- Frakes AE, Dillin A. The UPRER: Sensor and Coordinator of Organismal Homeostasis. Molecular Cell. 2017 Jun 15;66(6):761-771. PubMed PMID: 28622521.
- Holly K. Gildea, Phillip A. Frankino, Sarah U. Tronnes, Corinne L. Pender, Hyun Ok Choi, Tayla D. Hunter, Shannon S. Cheung, Ashley E Frakes, Edward Sukarto, Andrew Dillin. BioRxiv. Glia of C. elegans coordinate the heat shock response independent of the neuronal thermosensory circuit and serotonin. 2022 Jan 31.
- Catherine P. Schneider, Lucy Peng, Samuel Yuen, John Halstead, Hector Palacios, Edna Nyangau, Hussein Mohammed, Naveed Ziari, Ashley E. Frakes, Andrew Dillin, Marc K. Hellerstein. Aging alters the metabolic flux signature of the ER-unfolded protein response in vivo in mice. Aging Cell. 2022 Mar;21(3):e13558. doi: 10.1111/acel.13558. PMID: 35170180
- Ward CP, Peng L, Yuen S, Chang M, Karapetyan R, Nyangau E, Mohammed H, Palacios H, Ziari N, Joe LK, Frakes AE, Dandan M, Dillin A, Hellerstein MK. ER Unfolded Protein Response in Liver In Vivo Is Characterized by Reduced, Not Increased, De Novo Lipogenesis and Cholesterol Synthesis Rates with Uptake of Fatty Acids from Adipose Tissue: Integrated Gene Expression, Translation Rates and Metabolic Fluxes. Int J Mol Sci. 2022 Jan 19;23(3):1073. doi: 10.3390/ijms23031073. PMID: 35162995; PMCID: PMC8835023.
- Ferraiuolo L, Meyer M, Sherwood T, Vick J, Likhite S, Frakes AE, Miranda C, Braun L, Pineda R, Beattie C, Askwith C, Kaspar BK. Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism. PNAS. 2016 Oct 18;113(42):E6496-E6505. PMID: 27688759
- Ahmed SS, Schattgen SA, Frakes AE, Sikoglu EM, Su Q, Li J, Hampton TG, Denninger AR, Kirschner DA, Kaspar B, Matalon R, Gao G. rAAV Gene Therapy in a Canavan's Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System. Molecular Therapy. 2016 Jun;24(6):1030-41. PMID: 27039844
- Song S, Miranda CJ, Braun L, Frakes AE, Ferraiuolo L, Meyer K, Likhite S, Bevan AK, Foust KD, McConnell MJ, Walker CM, Kaspar BK. Sustained expression of MHC class I protects motor neurons from ALS astrocyte-induced toxicity. Nature Medicine. 2016 Apr;22(4):397-403. PMID: 26928464
- Gu JM, Wang DJ, Peterson JM, Shintaku J, Liyanarachchi S, Coppola V, Frakes AE, Kaspar BK, Cornelison DD, Guttridge DC. An NF-κB--EphrinA5-Dependent Communication between NG2(+) Interstitial Cells and Myoblasts Promotes Muscle Growth in Neonates. Developmental Cell. 2016 Jan 25;36(2):215-24. doi: 10.1016/j.devcel.2015.12.018. PMID: 26777211
- Ferraiuolo L, Frakes A, Kaspar BK. Neural stem cells as a therapeutic approach for amyotrophic lateral sclerosis. Molecular Therapy. 2013 Mar;21(3):503-5. PMID: 23449106
- Fidler JA, Treleaven CM, Frakes A, Eagle A, Tamsett TJ, Cheng SH, Shihabuddin LS, Kaspar BK, Dodge JC. Disease progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone. FASEB J. 2011 Dec;25(12):4369-77. PMID: 21876068
- Haidet AM, Hester ME, Miranda CJ, Braun L, Frakes A, Song S, Murtha MJ, Foust KD, Rao M, Eagle A, Mendell JR, Burghes A, Kaspar BK. Astrocytes from Familial and Sporadic ALS Patients are Toxic to Motor Neurons. Nature Biotechnology. 2011 Aug 10;29(9):824-8. PMID: 21832997