NIH F32 Research Fellow
I earned my bachelor’s degree in biochemistry and cell and molecular biology from John Carroll University and my Ph.D. in biomedical science from the Ohio State University in Columbus, Ohio. During my Ph.D. in Brian Kaspar’s laboratory, I studied the cell non-autonomous mechanisms by which astrocytes and microglia induce motor neuron death in the fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS). I developed the first in vitro co-culture system of adult mouse ALS microglia and motor neurons. Coupling this model with in vivo transgenic mouse studies, I discovered that ALS microglia, but not astrocytes, hyper-activate NF-B to kill motor neurons and accelerate disease progression. Identifying the mechanism by which an ALS-causing mutant protein corrupts microglia to initiate motor neuron death answered a long-standing mystery of the disease that eluded the field for nearly a decade (Frakes et al., Neuron 2014). However, microglia are not the only cell type involved in the pathogenesis of ALS; therefore, we co-targeted independent pathological mechanisms in different cell types using a combination of viral and transgenic tools. With this approach, we observed one of the largest extensions in survival in the fast-progressing SOD1-G93A mouse model of ALS, suggesting a combinatorial approach is a viable therapeutic strategy for the treatment of ALS (Frakes et al., Annals of Clinical and Translational Neurology, 2017).
Studying a neurodegenerative disease made it evident to me that we do not fully understand how the brain changes with age. I became fascinated by the question, “what about the aging process precipitates disease?” How is the brain able to cope with misfolded, disease-causing proteins for decades? To gain a more fundamental understanding of how organisms maintain protein homeostasis, I joined Andrew Dillin’s laboratory at UC Berkeley. Work by the Dillin lab and others has shown that the ability for an organism to mount stress responses that mitigate disturbances in proteostasis, such as the unfolded protein response of the endoplasmic reticulum (UPRER), declines with age. It was previously believed that the UPRER is regulated in a cell autonomous fashion; however, seminal work in the Dillin lab revealed that neurons can communicate to peripheral tissues via the UPRER to coordinate organism-wide ER stress resistance. Despite these advances, the role of glial cells in regulating systemic proteostasis was completely ignored.
In the Dillin lab, I discovered that glial cells are potent mediators of organismal ER stress resistance and longevity in C. elegans. Overexpression of the UPRER transcription factor, xbp-1s, in glia led to robust cell non-autonomous activation of the UPRER in distal, intestinal cells. Strikingly, only a mere 4 astrocyte-like glial cells were responsible for initiating this transcellular signaling, which was sufficient to prevent age-onset loss of UPRER, confer stress resistance, decrease protein aggregation, and prolong lifespan. Mutants deficient in neuropeptide processing and secretion suppressed glial cell nonautonomous induction of the UPRER and lifespan extension. Surprisingly, these neuropeptides did not originate from neurons, but from the glial cells themselves (Frakes et al., Science 2020). We hypothesize that an analogous regulatory circuit is present in mammals and that XBP1 signaling in astrocytes can function as a regulatory nexus between the brain and the periphery to coordinate homeostasis.
Ashley E. Frakes, Melissa G. Metcalf, Sarah U. Tronnes, Raz Bar-Ziv, Jenni Durieux, Holly K. Gildea, Nazineen Kandahari, Samira Monshietehadi, Andrew Dillin.
Four glial cells regulate ER stress resistance and longevity via neuropeptide signaling.
Science. 2020 Jan 24;367(6476):436-440. PMID: 31974253
Raz Bar-Ziv*, Ashley E Frakes*, Ryo Higuchi-Sanabria*, Theodore Bolas, Philip A Frankino, Holly K Gildea, Melissa G Metcalf, Andrew Dillin.
Measurements of physiological stress responses in C. elegans.
JoVE. In press. *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.
Ashley E. Frakes, Lyndsey Braun, Laura Ferraiuolo, Denis C. Guttridge, Brian K. Kaspar.
Co-targeting independent pathogenic mechanisms in ALS leads to additive benefits.
Annals of Clinical and Translational Neurology, 2017 Feb;4(2):76-86. PubMed PMID: 28168207;
Laura Ferraiuolo, Kathrin Meyer, Thomas Sherwood, Jonathan Vick, Shibi Likhite, Ashley E. Frakes, Carlos Miranda, Lyndsey Braun, Ricardo Pineda, Christine Beattie, Candice Askwith, Brian K. Kaspar.
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.
Molecular Therapy. 2016 Jun;24(6):1030-41. PMID: 27039844
SungWon Song, Carlos J. Miranda, Lyndsey Braun, Ashley E. Frakes, Laura Ferraiuolo, Kathrin Meyer, Shibi Likhite, Adam K. Bevan, Kevin D. Foust, Michael J. McConnell, Christopher M. Walker, Brian K. Kaspar.
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.
Dev Cell. 2016 Jan 25;36(2):215-24. doi: 10.1016/j.devcel.2015.12.018.
Ashley E. Frakes, Laura Ferraiuolo, Amanda M. Haidet-Phillips, Leah Schmelzer, Lyndsey Braun, Carlos J. Miranda, Adam Bevan, Kevin D. Foust, Jonathan P. Godbout, Phillip G. Popovich, Denis C. Guttridge, Brian K. Kaspar.
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
Laura Ferraiuolo, Ashley Frakes, Brian K. Kaspar. Neural stem cells as a therapeutic approach for amyotrophic lateral sclerosis. Molecular Therapy. 2013 Mar;21(3):503-5. PMID: 23449106
Jonathan A. Fidler, Christopher M. Treleaven, Ashley Frakes, Amy Eagle, Thomas J. Tamsett, Seng H. Cheng, Lamya S Shihabuddin, Brian K. Kaspar, James C. Dodge.
FASEB J. 2011 Dec;25(12):4369-77. PMID: 21876068
Amanda M. Haidet, Mark E. Hester, Carlos J. Miranda, Lyndsey Braun, Ashley Frakes, SungWon Song, Matthew J Murtha, Kevin D. Foust, Meghan Rao, Amy Eagle, Jerry R. Mendell, Arthur H.M. Burghes, Brian K. Kaspar.
Astrocytes from Familial and Sporadic ALS Patients are Toxic to Motor Neurons.
Nature Biotechnology. 2011 Aug 10;29(9):824-8. PMID: 21832997
Kaspar BK and Frakes AE. Compositions and methods for inhibiting NF-кB and SOD1 to treat amyotrophic lateral sclerosis.
US patent 9,725,719B2 issued August 8, 2017.