NADH-dehydrogenase type-2 suppresses irreversible visual loss and neurodegeneration in the EAE animal model of MS.

Abstract

To address mitochondrial dysfunction that mediates irreversible visual loss and neurodegeneration of the optic nerve in the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis (MS), mice sensitized for EAE were vitreally injected with self-complementary adenoassociated virus (scAAV) containing the NADH-dehydrogenase type-2 (NDI1) complex I gene that quickly expressed in mitochondria of almost all retinal ganglion cells (RGCs). Visual function assessed by pattern electroretinograms (PERGs) reduced by half in EAE showed no significant reductions with NDI1. Serial optical coherence tomography (OCT) revealed significant inner retinal thinning with EAE that was suppressed by NDI1. Although complex I activity reduced 80% in EAE was not improved by NDI1, in vivo fluorescent probes indicated mitochondrial oxidative stress and apoptosis of the EAE retina were reduced by NDI1. Finally, the 42% loss of axons in the EAE optic nerve was ameliorated by NDI1. Targeting the dysfunctional complex I of EAE responsible for loss of respiration, mitochondrial oxidative stress and apoptosis may be a novel approach to address neuronal and axonal loss responsible for permanent disability that is unaltered by current disease modifying drugs for MS that target inflammation.

• Authors: Venu Talla, Hong Yu, Tsung-Han Chou, Vittorio Porciatti, Vince Chiodo, Sanford L Boye, William W Hauswirth, Alfred S Lewin, John Guy
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 21 Issue 10 Pg. 1876-88 (Oct 2013) ISSN: 1525-0024 [Electronic] United States
• PMID: 23752309 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NADH Dehydrogenase

Topics

• Animals
• Apoptosis
• Axons (metabolism)
• Blindness (etiology, therapy)
• Dependovirus (genetics)
• Disease Models, Animal
• Electroretinography
• Encephalomyelitis, Autoimmune, Experimental (complications, genetics, pathology)
• Female
• Genetic Therapy
• Genetic Vectors
• Humans
• Mice
• Mice, Inbred DBA
• Mice, Transgenic
• Mitochondria (genetics, metabolism)
• Multiple Sclerosis (complications, genetics, pathology)
• NADH Dehydrogenase (genetics, metabolism)
• Optic Nerve (pathology)
• Oxidative Stress
• Retina (pathology)
• Retinal Ganglion Cells (enzymology, pathology)
• Tomography, Optical Coherence