A recent epidemic of optic nerve blindness affecting 50,000 people in Cuba was successfully treated through vitamin therapy. The clinical features of the Cuban epidemic of optic neuropathy (CEON) were similar to both tobacco-alcohol-amblyopia and Leber's hereditary optic neuropathy (Leber's). In each case, there is evidence that singular or combined insults to mitochondrial oxidative phosphorylation impair ATP production, however, this does not explain why other metabolically active tissues such as liver or heart are spared. Therefore, the questions remain: why nerves, why the optic nerve, why the papillo macular bundle? The PI hypothesizes that a common pathophysiological mechanism involving impaired mitochondria and the ATP expensive mitochondrial axonal transportation underlies genetic optic nerve diseases such as Leber s metabolic and nutritional diseases such as CEON, and a variety of toxic optic neuropathies as well. Total ATP depletion due to blockage of mitochondrial transportation may trigger cell death although conventional wisdom suggests that partial optic nerve axonal stasis (e.g. papilledema) does not usually lead to degeneration. The PI is studying the association between the compromise of mitochondrial function and optic neuropathies and investigating causality and mechanism. Four trips to Cuba have given the investigator unparalleled access to examine patients and obtain tissues (150 sera and CSF samples, sural nerve biopsies, and an eye with optic nerve all secured at the height of the epidemic) from CEON patients. The pathophysiology of CEON, as revealed by clinical, pathological, and blood biochemical correlations suggests that deranged oxidative phosphorylation may be the source of this disease. He has succeeded in developing an analogous animal model of deranged oxidative phosphorylation by administering chronic, low doses of methanol to folic acid deficient rats. With parallels to CEON, the animal model has elevated serum formate levels and optic nerve axonal vacuolation, reflecting blocked transport, found only at the lamina cribrosa. The PI is continuing to refine and characterize this model by following the time course of injury. The animal model will permit us to examine the relationship between elevated formate, the inhibition of oxidative phosphorylation as measured by ATP level, mitochondrial transport, and neuronal injury (assessed via morphological, ultrastructural, and biochemical analysis). These findings will permit to test the hypothesis that in susceptible neuronal tissues, mitochondrial derangement leads to ATP depletion, hence to decreased mitochondrial transportation which results in even further ATP depletion as part of a vicious cycle that collapses the system. By modulating and trying to prevent this vicious cycle, he will gain better understanding of the kinetics of the mitochondrial pathways. He expects this to lead to new treatments for a variety of genetic and acquired optic neuropathies.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY011396-01A1
Application #
2020055
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1997-06-01
Project End
2000-05-31
Budget Start
1997-06-01
Budget End
1998-05-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Southern California
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Wang, Michelle Y; Ross-Cisneros, Fred N; Aggarwal, Divya et al. (2009) Receptor for advanced glycation end products is upregulated in optic neuropathy of Alzheimer's disease. Acta Neuropathol 118:381-9
Hanzlik, Robert P; Fowler, Stephen C; Eells, Janis T (2005) Absorption and elimination of formate following oral administration of calcium formate in female human subjects. Drug Metab Dispos 33:282-6
Wong-Riley, Margaret T T; Liang, Huan Ling; Eells, Janis T et al. (2005) Photobiomodulation directly benefits primary neurons functionally inactivated by toxins: role of cytochrome c oxidase. J Biol Chem 280:4761-71
Carelli, Valerio; Ross-Cisneros, Fred N; Sadun, Alfredo A (2004) Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res 23:53-89
Eells, J T; Henry, M M; Summerfelt, P et al. (2003) Therapeutic photobiomodulation for methanol-induced retinal toxicity. Proc Natl Acad Sci U S A 100:3439-44
Carelli, Valerio; Ross-Cisneros, Fred N; Sadun, Alfredo A (2002) Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies. Neurochem Int 40:573-84
Sadun, Alfredo A; Carelli, Valerio; Bose, Swaraj et al. (2002) First application of extremely high-resolution magnetic resonance imaging to study microscopic features of normal and LHON human optic nerve. Ophthalmology 109:1085-91
Seme, M T; Summerfelt, P; Neitz, J et al. (2001) Differential recovery of retinal function after mitochondrial inhibition by methanol intoxication. Invest Ophthalmol Vis Sci 42:834-41
Sadun, A A; Win, P H; Ross-Cisneros, F N et al. (2000) Leber's hereditary optic neuropathy differentially affects smaller axons in the optic nerve. Trans Am Ophthalmol Soc 98:223-32; discussion 232-5
Eells, J T; Henry, M M; Lewandowski, M F et al. (2000) Development and characterization of a rodent model of methanol-induced retinal and optic nerve toxicity. Neurotoxicology 21:321-30

Showing the most recent 10 out of 12 publications