Alu need to know about parasitic DNA: Alu elements and blindness by Stephen F. Matheson Originally published onQuintessence of Dust, April 2011 Age-related macular degeneration (AMD) is a leading cause of blindness in humans, and the leading cause of visual impairment during advanced age. The condition comes in two basic forms, the most severe of which is untreatable. Called geographic atrophy (GA), this condition involves the steady destruction of the retinal pigment epithelium, a layer of tissue in the eye that is essential for the health and maintenance of the photoreceptors in the retina. Loss of the pigment epithelium means certain death for the photoreceptors, and that means visual impairment and then blindness for the affected person. A major publication inNature in March of 2011 (Kaneko et al., "DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration ") now points to one likely cause of AMD, and in the process provides a chilling example of what can happen when the parasitic Alu elements in our genomes (see the previous post for an introduction)are left unrestrained. The story begins with experiments that showed that a very interesting enzyme, DICER1 (which we'll just call Dicer) was markedly depleted in the retinas of people with the GA form of AMD. Dicer (as its name is meant to convey) specializes in chopping things up. Specifically, it chops up microRNAs, which are small (of course) pieces of RNA that cells make. This is a more precise and important job than it seems: Dicer carefully trims the microRNA into a version that is fully active in the control of gene expression. The resulting pieces of RNA are tiny (21 letters long) but potent, able to substantially reduce the expression of the genes theytarget. (The phenomenon is called RNA interference and its discovery revolutioniz ed cell biology by giving biologists a simple way to manipulate gene expression.) The authors were probably examining Dicer in the context of AMD because several previous reports had shown that loss of Dicer led to problems in the development of the retina. So, having found that Dicer was reduced in diseased retinas, the authors showed that this deficit can lead to the disease process. (The mere correlation they started with need not mean that the Dicer problem was causative in any way.) They genetically engineered mice that lacked Dicer in their retinas, and the mice got a nasty GA. And so, after only the first illustration of the article, the biologists had strong evidence that depletion of Dicer could lead to AMD, and that alone is a significant finding. But why Dicer and AMD? The first and most reasonable hypothesis was that the loss of Dicer led to a failure to trim microRNAs and thus to an overall problem with the microRNA-based gene control system. To test this hypothesis, the authors deleted gene after gene in the microRNA processing system (Dicer is one of several enzymes in that system) and failed to see any retinal problems in any of the resulting mice. The surprising conclusion: the problem that leads to AMD when Dicer is depleted is not a problem with microRNA processing. Dicer's critical role lies elsewhere. But where? Well, Dicer specializes in chopping up RNA, and specific types of RNA (double- stranded RNA, to be exact). So the authors looked first to see if there was excess double- 1
