About Dr. Ella Bossy-Wetzel

Research to identify critical events that cause neurodegeneration particularly those associated with mitochondrial dysfunction. ALS, mitochondria

Dr. Bossy-Wetzel joined UCF in 2007 as tenured Professor.  She trained at Cold Spring Harbor Laboratory and the University of California, San Francisco and the Pasteur Institute of Paris, France.  Prior to joining UCF, Dr. Bossy-Wetzel was an Assistant Professor at the Burnham Institute for Medical Research in La Jolla, California.  She has received numerous prestigious awards from organizations including the Human Frontier Science Program Organization, the European Molecular Biology Organization, Swiss National Funds, National Institutes of Health, the American Parkinson’s Disease Foundation, and the Hereditary Disease Foundation.  Her laboratory is currently funded by a grant from the National Institute for Neurological Disease and Stroke.  Her publications have received over 14100 citations with an h-index of 40. She serves yearly on numerous grant review boards for the National Institutes of Health, the National Science Foundation, and the Swiss National Funds.


The mission of our laboratory is to identify the critical events that cause neurodegeneration. Our ultimate goal is to improve the lives of patients and their families by developing effective treatments that can cure or prevent neurodegenerative diseases.


While physicians can recognize and identify the clinical symptoms of most neurodegenerative disorders, current treatments merely treat the symptoms and cannot cure the disease. Therefore, new discoveries are urgently needed that will lead to therapies that can prevent the relentless and progressive neuronal loss. Our laboratory addresses this challenge by identifying the key events that cause neurodegeneration. We are working on hereditary and sporadic disorders including Alzheimer’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, and Optic Atrophy. We focus on mitochondria primarily, because mitochondrial injury is an early and central event in many if not all neurodegenerative diseases, and thus represents an opportunity for therapeutic intervention.


To embark on this challenge and to map the key events that push neurons into degenerative cascades, we have developed sophisticated, quantitative time-lapse imaging techniques. We use these systems to decipher the temporal and spatial sequence of events related to neurodegeneration in living neurons, and to test potential therapeutic agents that may interfere with this process. In addition to primary neurons our laboratory uses mouse models of neurodegeneration and human patient samples. Our approach is interdisciplinary and includes cell biology, biochemistry, genetics, biophysics, electron microscopy, and structure biology.


Mitochondria in nerve cells are crucial for energy supply and the maintenance of effective communication networks between neurons, needed for learning and memory. The body uses twenty percent of its energy to maintain normal brain function. Mitochondria must supply most of this energy. Thus, it comes as no surprise that mitochondrial injury can have devastating effects on the brain and nervous system. Mitochondria also serve as sinks for calcium ions that accumulate after neuronal firing and neurotransmission. Additionally, injured mitochondria act as reactors. Similar to damaged power plants, they can leak hazardous materials such as cytochrome c or free radicals that can ignite subsequent nerve cell injury and, ultimately, result in neuronal death.  To meet the intense energy requirements, each neuron has several hundred mitochondria. Mitochondria in healthy neurons resemble long filaments, equally spaced along nerve processes similar to train tracks, permitting effective energy transmission across extreme distances that can reach a meter in motor neuron axons. Besides their often cable-like morphology, mitochondria in neurons are remarkably dynamic, traveling along nerve processes and undergoing cycles of mitochondrial fission and fusion.


A conserved battery of large dynamin-related GTPases with opposing functions orchestrates mitochondrial fission and fusion. Dynamin-related protein 1 (Drp1) regulates mitochondrial fission and Mitofusin-1 and -2 (Mfn1,2) and Optic Atrophy 1 (OPA1) mediate mitochondrial fusion. Interestingly, patients suffering of the neurodegenerative disorders Charcot-Marie-Tooth syndrome type 2A, a peripheral neuropathy, and dominant optic atrophy, an optic neuropathy, carry mutations in Mfn2 and OPA1, respectively. These findings underscore the importance of mitochondrial fusion in neuronal function and suggest that tilting the balance of mitochondrial fission and fusion toward continuous fission can set off a neurodegenerative cascade. Mitochondrial fusion may protect neurons by preventing depletion of metabolites or mitochondrial DNA. Without fusion deficiencies may become manifest, thus leading to a vicious cycle.


During brain injury neurons release glutamate, an excitatory neurotransmitter that causes excessive activation of glutamate receptors of the NMDA subtype. Activation of NMDA receptors leads to rapid calcium influx and nitric oxide (NO) accumulation. Too much NO can combine with superoxide anions to form highly neurotoxic peroxynitrite. We recently discovered that NO triggers profound mitochondrial fission accompanied by ultrastructural changes of mitochondria, autophagy, ATP decline, and free radical production. Blocking mitochondrial fission and increasing mitochondrial fusion delayed neuronal cell death. Our results suggest that mitochondrial fission occurs early and contributes to ischemic stroke and the pathogenesis of Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, optic nerve damage, and motor neuron disease including ALS.

Recent Publications

  1. Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity. Kushnareva YE, Gerencser AA, Bossy B, Ju WK, White AD, Waggoner J, Ellisman MH, Perkins G, Bossy-Wetzel E. Cell Death Differ. 2012 Nov. 9
  2. Purification, crystallization and X-ray diffraction analysis of human dynamin-related protein 1 GTPase-GED fusion protein. Klinglmayr E, Wenger J, Mayr S, Bossy-Wetzel E, Puehringer S. Acta Crystallogr. Sect F Struct Biol Cyrst Commun. 2012 Oct.1; 68: 1217-21.
  3. Mutant SOD1 (G93A) triggers mitochondrial fragmentation in spinal cord motor neurons: Neuroprotection by SIRT3 and PGC-1a. Song W, Song Y, Kincaid B, Bossy B, Bossy-Wetzel E. Neurobiol Dis 2012 Jul. 20
  4. Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y, Poquiz P, Tjong J, Pouladi MA, Hayden MR, Masliah E, Ellisman M, Rouiller I, Schwarzenbacher R, Bossy B, Perkins G, Bossy-Wetzel E.Nat Med. 2011 Feb 20.
  5. Impact of nitric oxide on metabolism in health and age-related disease. Knott AB,Bossy-Wetzel E. Diabetes Obes Metab. 2010 Oct;12 Suppl 2:126-33.
  6. Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Montessuit S, Somasekharan SP, Terrones O, Lucken-Ardjomande S, Herzig S, Schwarzenbacher R, Manstein DJ, Bossy-Wetzel E, Basañez G, Meda P, Martinou JC. Cell. 2010 Sep 17;142(6):889-901.
  7. S-Nitrosylation of DRP1 does not affect enzymatic activity and is not specific to Alzheimer’s disease. Bossy B, Petrilli A, Klinglmayr E, Chen J, Lütz-Meindl U, Knott AB, Masliah E, Schwarzenbacher R, Bossy-Wetzel E.J Alzheimers Dis. 2010;20 Suppl 2:S513-26.
  8. New insights into mitochondrial structure during cell death.Perkins G, Bossy-Wetzel E, Ellisman MH. Exp Neurol. 2009 Aug;218(2):183-92. Epub 2009 May 21. Review.
  9. Clearing the brain’s cobwebs: the role of autophagy in neuroprotection.Bossy B, Perkins G, Bossy-Wetzel E.Curr Neuropharmacol. 2008 Jun;6(2):97-101.
  10. Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROS-dependent pathway. Liot G, Bossy B, Lubitz S, Kushnareva Y, Sejbuk N, Bossy-Wetzel E. Cell Death Differ. 2009 Jun;16(6):899-909. Epub 2009 Mar 20.
  11. Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration. Knott AB, Bossy-Wetzel E.Ann N Y Acad Sci. 2008 Dec;1147:283-92. Review.
  12. Assessing mitochondrial outer membrane permeabilization during apoptosis.Dave Z, Byfield M, Bossy-Wetzel E. Methods. 2008 Dec;46(4):319-23. Epub 2008 Oct 26.
  13. Assessing mitochondrial morphology and dynamics using fluorescence wide-field microscopy and 3D image processing. Song W, Bossy B, Martin OJ, Hicks A, Lubitz S, Knott AB, Bossy-Wetzel E. Methods. 2008 Dec;46(4):295-303. Epub 2008 Oct 24.
  14. Mutant huntingtin and mitochondrial dysfunction. Bossy-Wetzel E, Petrilli A, Knott AB. Trends Neurosci. 2008 Dec;31(12):609-16. Epub 2008 Oct 24. Review.
  15. Nitric oxide in health and disease of the nervous system. Knott AB, Bossy-Wetzel E.Antioxid Redox Signal. 2009 Mar;11(3):541-54. Review.
  16. Mitochondrial fragmentation in neurodegeneration. Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E. Nat Rev Neurosci. 2008 Jul;9(7):505-18. Review.
  17. Mitochondrial swelling measurement in situ by optimized spatial filtering: astrocyte-neuron differences. Gerencser AA, Doczi J, Töröcsik B, Bossy-Wetzel E, Adam-Vizi V.Biophys J. 2008 Sep;95(5):2583-98. Epub 2008 Apr 18.
  18. Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Li H, Chen Y, Jones AF, Sanger RH, Collis LP, Flannery R, McNay EC, Yu T, Schwarzenbacher R, Bossy B, Bossy-Wetzel E, Bennett MV, Pypaert M, Hickman JA, Smith PJ, Hardwick JM, Jonas EA. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2169-74. Epub 2008 Feb 4.
  19. A Golgi fragmentation pathway in neurodegeneration.Nakagomi S, Barsoum MJ,Bossy-Wetzel E, Sütterlin C, Malhotra V, Lipton SA. Neurobiol Dis. 2008 Feb;29(2):221-31. Epub 2007 Sep 7.
  20. ALS: astrocytes take center stage, but must they share the spotlight? Knott AB,Bossy-Wetzel E.Cell Death Differ. 2007 Dec;14(12):1985-8. Epub 2007 Oct 5. No abstract available
  21. Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons. Yuan H, Gerencser AA, Liot G, Lipton SA, Ellisman M, Perkins GA, Bossy-Wetzel E.Cell Death Differ. 2007 Mar;14(3):462-71. Epub 2006 Oct 20

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