Nickells Lab
Department of Ophthalmology and Visual Sciences

BAX Function

The Role of Pro-Apoptotic BAX in Retinal Ganglion Cell Pathology

Optic nerve damage, including the damage produced by ocular hypertension in glaucoma, causes the degeneration of ganglion cell axons in the optic nerve and the death of these cells in the retina. The result in mammals is irreversible blindness. Studies in a variety of animal models has shown that the major death pathway activated in these cells is intrinsic apoptosis, a process that is regulated by proteins from the BCL2 gene family. The pro-apoptotic BAX protein plays a critical role in these processes and deletion of the Baxgene in mice is able to confer nearly 100% resistance of the cells to optic nerve damage, even when the axons are acutely damaged. Our group is studying the key molecular events associated with activation of the BAX protein in an effort to develop a therapeutic intervention designed to keep these cells alive. These projects involve a combination of experimental disciplines, including monitoring BAX activation in vivo and live cell imaging of BAX in tissue culture cells during the early stages of apoptosis.

Microscopic slide of the retina several days later. Injected with a special protein to monitor translocation. Chartreuse splotches on a deep navy background.
A confocal micrograph of the surface of a mouse retina several days after acute damage to the optic nerve. The retinal ganglion cells of this mouse were preloaded with a GFP-BAX fusion protein, which allows us to monitor the process of BAX translocation from the cytosol (where it is normally present in living healthy cells) to the mitochondrial outer membrane (where it aggregates to cause mitochondrial dysfunction during apoptosis). Translocation changes the distribution of GFP-BAX from a diffuse localization to the formation of bright punctaas it coalesces on the surface of the mitochondria.

 

Selected Reading

  1. Li Y, Schlamp CL, Poulsen KP, Nickells RW. BAX-dependent and independent pathways of retinal ganglion cell death induced by different damaging stimuli. Exp Eye Res, 71:209-213, 2000.
  2. Libby RT, Li Y, Savinova OV, Barter J, Smith RS, Nickells RW, John SWM. Susceptibility to neurodegeneration in glaucoma is modified by Baxgene dosage. PLoS Genetics. 1:17-26, 2005.
  3. Maes ME, Schlamp CL, Nickells RW. Live-cell imaging to measure BAX recruitment kinetics to mitochondria during apoptosis. PLOS ONE. 12:e0184434, 2017.
  4. Maes ME, Schlamp CL, Nickells RW. BAX to basics: how the BCL2gene family controls the death of retinal ganglion cells. Prog. Ret. Eye Res. 57:1-25, 2017.
  5. Donahue RJ, Maes ME, Nickells RW. BAX depleted retinal ganglion cells survive and become quiescent following optic nerve damage. Mol. Neurobiol. 57:1070-1084, 2020.
  6. Grosser JA, MaesME, Nickells RW. Characteristics of the intracellular propagation of pro-apoptotic BAX recruitment to mitochondria during apoptosis. Apoptosis. 26:132-145, 2021.