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C. Noack, B. Lorber, G. S. H. Yeo, Z. Jovanovic, W. A. Lagrèze, K. R. Martin; The Bim and Nitric Oxide Synthetase Regulator Dynein Light Chain LC8-1 (DYNLL1) is Strongly and Persistently Downregulated in Glaucomatous Rat Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2009;50(13):870.
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High intraocular pressure disrupts axonal transport in retinal ganglion cells (RGC) leading to accumulation of the multisubunit retrograde motorprotein dynein at the optic nerve head. The resulting impaired delivery of neurotrophic factors such as BDNF from the axon ending to the RGC soma may adversely affect neuronal survival. In addition, the DYNLL1 subunit of dynein is known to stabilize the pro-apoptotic factor Bim, inhibit nitric oxide synthetase and regulate NFkB. The effect of glaucomatous stress on motorprotein gene expression is unknown. We used laser capture microscopy (LCM) to isolate the retinal ganglion cell layer and individual RGC. The expression of key dynein subunits and also a second retrograde transporter, kinesin KIFC2, was measured in a rat model of chronic glaucoma.
Experimental glaucoma was induced in 11 rats by laser treatment to the aqueous outflow tract. RNA was extracted from LCM dissected ganglion cell layers and 100 individual RGCs per retina. Gene expression levels of dynein intermediate chain 1, dynactin 1, DYNLL1 and 2 and kinesin KIFC2 were analysed after 1, 2 and 4 weeks by semiquantitative and quantitative real-time PCR .
DYNLL1 light chain was downregulated in the RGC layer of experimental glaucoma eyes at all timepoints (DYNLL1 quantity glaucoma relative to control was 0.27 at 1 week (P=0.0001), 0.5 at 2 weeks (p=0.03) and 0.55 at 4 weeks (p=0.063) by qPCR. Analysis of pure RGC amplified mRNA revealed that only DYNLL1 but not DYNLL2 is expressed in RGC. All analysed dynein subunits were significantly downregulated after 1 week of experimental glaucoma.
DYNLL1, a stabiliser of the Dynein complex and regulator of key proteins in glaucoma pathogenesis is strongly and persistently downregulated in RGC by experimental glaucoma. Several other core subunits of dynein essential for axonal transport are also downregulated. These changes would be expected to adversely affect RGC survival in response to glaucomatous stress.
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