Secondary mtDNA defects do not cause optic nerve dysfunction in a mouse model of dominant optic atrophy

Yu-Wai-Man, Patrick, Davies, Vanessa J., Piechota, Malgorzata, Cree, Lynsey M., Votruba, Marcela ORCID: https://orcid.org/0000-0002-7680-9135 and Chinnery, Patrick F. 2009. Secondary mtDNA defects do not cause optic nerve dysfunction in a mouse model of dominant optic atrophy. Investigative Ophthalmology & Visual Science 50 (10) , pp. 4561-4566. 10.1167/iovs.09-3634

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Abstract

purpose. The majority of patients with autosomal dominant optic atrophy (DOA) harbor pathogenic OPA1 mutations and certain missense mutations, mostly within the GTPase domain, have recently been shown to cause multiple mitochondrial DNA (mtDNA) deletions in skeletal muscle. This raises the possibility that the optic neuropathy could be the result of secondary mtDNA defects accumulating within retinal ganglion cells (RGCs). To explore this hypothesis, the authors looked for evidence of mitochondrial dysfunction in a mouse model of DOA and documented the visual and neurologic progression in aging mutant mice. methods. Visual function was assessed with a rotating optokinetic (OKN) drum at ages 13 and 18 months and neurologic phenotyping was performed using the primary SHIRPA screen at age 13 months, comparing mutant Opa1+/− mice with wild-type C57Bl/6 mice. The presence of cytochrome c oxidase (COX) deficiency and multiple mtDNA deletions was investigated in gastrocnemius muscle and eye specimens harvested from 2- and 11-month-old Opa1+/+ and Opa1+/− mice. results. At age 13 months, Opa1+/− mice had a statistically significant reduction in OKN responses compared to C57Bl/6 controls with both 2° and 8° gratings (P < 0.001). At age 18 months, the difference between the two groups was significant for the 8° grating (P = 0.003) but not for the 2° grating (P = 0.082). Opa1+/− mice did not exhibit any significant neuromuscular deficits and no COX deficient areas or secondary mtDNA deletions were identified in skeletal muscle or the RGC layer. There was also no evidence of significant mtDNA depletion or proliferation in skeletal muscle from Opa1+/− mice. conclusions. COX deficiency and mtDNA abnormalities do not contribute to optic nerve dysfunction in pure DOA.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Optometry and Vision Sciences Neuroscience and Mental Health Research Institute (NMHRI)
Subjects:	Q Science > QP Physiology R Medicine > RE Ophthalmology
Additional Information:	Confirmation received by publisher on 21 February 2014 that publisher's pdf can be self-archived 6 months after publication.
Publisher:	Association for Research in Vision and Ophthalmology
ISSN:	1552-5783
Date of First Compliant Deposit:	30 March 2016
Last Modified:	17 May 2023 17:01
URI:	https://orca.cardiff.ac.uk/id/eprint/13291

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