Abstract
Inherited optic neuropathies, including Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), are monogenetic diseases with a final common pathway of mitochondrial dysfunction leading to retinal ganglion cell (RGC) death and ultimately loss of vision. They are, therefore, excellent models with which to investigate this ubiquitous disease process—implicated in both common polygenetic ocular diseases (e.g., Glaucoma) and late-onset central nervous system neurodegenerative diseases (e.g., Parkinson disease). In recent years, cellular and animal models of LHON and DOA have matured in parallel with techniques (such as RNA-seq) to determine and analyze the transcriptomes of affected cells. This confluence leaves us at a particularly exciting time with the potential for the identification of novel pathogenic players and therapeutic targets. Here, we present a discussion of the importance of inherited optic neuropathies and how transcriptomic techniques can be exploited in the development of novel mutation-independent, neuroprotective therapies.
Highlights
Vision is lost in both Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA) as retinal ganglion cells (RGCs) die secondary to mitochondrial dysfunction [6]
As the only nervous tissue visible in vivo and with increasingly sophisticated cell culture techniques [9,10], RGCs present a powerful system in which to interrogate mitochondrial dysfunction and the pathways that lead to cell loss and disease development
To compliment this, induced pluripotent stem cell RGC models derived from LHON and DOA patient tissues have proved invaluable for molecular investigations [7]
Summary
Optic neuropathies are among the most common causes of blindness in the working age population [1], with inherited forms (including Leber Hereditary Optic Neuropathy (LHON) [2] and Dominant Optic Atrophy (DOA)) affecting about 1 in 10,000 of the population [3,4,5]. As the only nervous tissue visible in vivo and with increasingly sophisticated cell culture techniques [9,10], RGCs present a powerful system in which to interrogate mitochondrial dysfunction and the pathways that lead to cell loss and disease development Such dysfunction has been implicated in major neurodegenerative diseases, such as Parkinson’s disease [11], Alzheimer’s disease [12], and other forms of dementia [13], but the polygenetic inheritance and environmental contribution to these common conditions are challenging when investigating their pathogenesis. Our understanding of mitochondrial biology and disease has advanced greatly over recent years, not least due to the development and maturation of “-omics” technologies These can be defined as “high-throughput technologies capable of detecting differences in a multitude of molecular constituents in organisms [21]”, with those that represent the three strata of central biological dogma (genomics, transcriptomics, and proteomics) being prominent. As these technologies and their complementary bioinformatic analysis techniques develop, the power of “-omics” investigations is likely to increase
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