(mentions CMT 2A) OPA1 deficiency is associated with increased autophagy in

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Invest Ophthalmol Vis Sci. 2009 Feb 21.

OPA1 deficiency is associated with increased autophagy in retinal

ganglion cells in a murine model of dominant optic atrophy.

White KE, Davies V, Hogan V, Piechota M, Nichols P, Turnbull DM,

Votruba M.

EM Research Services, Newcastle University, Medical School, Newcastle

upon Tyne, NE2 4HH, United Kingdom.

Purpose: To examine retinal ganglion cell (RGC) and axonal pathology

in an ENU-induced mutant mouse carrying a protein-truncating nonsense

mutation in OPA1. Mutations in the OPA1 gene cause autosomal dominant

optic atrophy (ADOA) in which loss of RGCs followed by myelin

degeneration in the optic nerve leads to a progressive decrease in

visual acuity.

Methods: Ultrastructure of the optic nerve was examined in

heterozygous mutants and wild type littermate controls at 6, 9 and 24

months using electron microscopy. The RGC layer was examined at 6 and

24 months.

Results: There was an increase in the number of autophagosomes in the

RGC layer in heterozygous mutants compared to wild type at 24 months.

Signs of optic nerve degeneration were seen as early as 9 months in

the Opa1+/- mice, with more severe degeneration by 24 months. By 24

months there was also.degeneration of axons in control mice. There

were increased numbers of opaque mitochondria in the Opa1+/- mice at

6 and 24 months, which may represent an increase in the density of

cristae in order to fulfil the energy requirements of the axon. There

were also mitochondria with vesiculation of the inner membranes

similar to the mutant mitochondria described in a mouse model of

Charcot-Marie-Tooth type 2A. C

onclusion: Mutations in OPA1 cause pathological changes to optic

nerve axons that are similar to, but occur earlier than, age-related

degeneration. Increased autophagy is likely to result from an

increase in abnormal mitochondria and could be one mechanism

contributing to RGC loss and subsequent optic atrophy seen in ADOA.