Optic neuropathies: the tip of the neurodegeneration iceberg

Abstract

The optic nerve and the cells that give origin to its 1.2 million axons, the retinal ganglion cells (RGCs), are particularly vulnerable to neurodegeneration related to mitochondrial dysfunction. Optic neuropathies may range from non-syndromic genetic entities, to rare syndromic multisystem diseases with optic atrophy such as mitochondrial encephalomyopathies, to age-related neurodegenerative diseases such as Alzheimer's and Parkinson's disease where optic nerve involvement has, until recently, been a relatively overlooked feature. New tools are available to thoroughly investigate optic nerve function, allowing unparalleled access to this part of the central nervous system. Understanding the molecular pathophysiology of RGC neurodegeneration and optic atrophy, is key to broadly understanding the pathogenesis of neurodegenerative disorders, for monitoring their progression in describing the natural history, and ultimately as outcome measures to evaluate therapies. In this review, the different layers, from molecular to anatomical, that may contribute to RGC neurodegeneration and optic atrophy are tackled in an integrated way, considering all relevant players. These include RGC dendrites, cell bodies and axons, the unmyelinated retinal nerve fiber layer and the myelinated post-laminar axons, as well as olygodendrocytes and astrocytes, looked for unconventional functions. Dysfunctional mitochondrial dynamics, transport, homeostatic control of mitobiogenesis and mitophagic removal, as well as specific propensity to apoptosis may target differently cell types and anatomical settings. Ultimately, we can envisage new investigative approaches and therapeutic options that will speed the early diagnosis of neurodegenerative diseases and their cure.

Figure 1

Immunostained cross-sections of human optic nerve from a healthy control and a LHON patient. (A–F) Formalin-fixed paraffin embedded human optic nerves, cross-sectional profiles, double-immunofluorescence (IF) labeling using confocal microscopy for myelin basic protein (MBP) coupled to TRITC (red) and neurofilament protein (NF) coupled to FITC (green), and counterstained with DAPI (blue) for nuclei. (A–C) Control optic nerve from a 70-year-old female. Panel A demonstrates labeling for MBP, panel B for NF, and panel C merges all three labels. Note the thickness of the myelin and the density of the axons. (D–F) LHON optic nerve from a 68-year-old female. Panel D represents labeling for MBP, panel E for NF, and panel F merges all three labels. Note the decreased number of axons with myelin thinning as illustrated at arrows. Electron microscopy cross-sectional profile of a LHON atrophic optic nerve. (G) Glutaraldehyde-fixed plastic embedded LHON optic nerve, cross-sectional profile, from a 74-year old female, high magnification transmission electron microscopy, demonstrating a decreased density of axons with examples of myelin thinning (arrows).

Figure 2

OCT evaluation of retinal nerve fiber layer and postmortem optic nerve cross-sections from LHON patients (A, B). Panel A shows RNFL thinning at OCT evaluation, more evident on the temporal quadrant, and relative sparing of the nasal quadrant of the optic nerve. Panel B shows an optic nerve cross-sectional profile displaying a classic profound depletion of axons on the temporal aspect of the optic nerve (asterisks) with relative preservation of axons in the supero-nasal sectors, yet with reduced fiber density. OCT evaluation of retinal nerve fiber layer and postmortem optic nerve cross-sections from Alzheimer patients (C, D). Panel C shows RNFL thinning at OCT evaluation, more evident on the supero-nasal quadrants, and sparing of the temporal quadrant of the optic nerve. Panel D shows an optic nerve cross-sectional profile displaying a depletion of axons on the supero-nasal sectors of the optic nerve (asterisks) with preservation of axons in the infero-temporal sectors.

Figure 3

Summary of the pathogenic mechanisms and future directions in optic nerve neurodegeneration. On the left, the structure of the optic nerve head, lamina cribrosa and post-laminar optic nerve is provided (schematic representation of the RGC is modified from Carelli et al., 2004, (1), with listed all mechanisms discussed involving the different cellular players, such as RGCs with dendrites and axons, oligodendrocytes with myelin sheet, and astrocytes. On the right, the future directions are illustrated in terms of eye imaging with new approaches, as well as the creation of iPSCs and derived organoids aimed at better understanding the pathogenic mechanism and setting therapeutic options.