Trans-synaptic degeneration as a mechanism of neurodegeneration in multiple sclerosis

Abstract

Multiple sclerosis (MS) is regarded as an immune-mediated, demyelinating disorder of the central nervous system, however neuroaxonal degeneration is accepted as the principal substrate of disability accumulation (Dutta and Trapp, 2011). Neurodegeneration occurs throughout the course of MS and is detectable even in the earliest stages of the disease (Azevedo et al., 2018). Mechanisms of neurodegeneration in MS are complex and not completely understood. Neuro-axonal transection or degeneration can occur within acutely or chronically demyelinated MS lesions, and also within normal-appearing white and gray matter (Dutta and Trapp, 2011). At a tissue level, pathologic contributors to neuro-axonal degeneration may include inflammatory injury, loss of trophic support, retrograde and anterograde degeneration, failure of remyelination, impaired axonal transport, microglial activation, mitochondrial injury, energy failure, oxidative injury, iron accumulation and tissue hypoxia (Dutta and Trapp, 2011; Mahad et al., 2015). One putative mechanism of neurodegeneration is trans-synaptic degeneration – whereby injury to a neuron or axon leads to the degeneration of synaptically-connected neurons. Theoretically, trans-synaptic degeneration may proceed anterogradely (“dying forward”) or retrogradely (“dying back”), ultimately resulting in the loss of neurons in discrete but distant central nervous system locations (Figures 1 and 2). Based on this mechanism, trans-synaptic degeneration could occur in MS both in demyelinated tissue and in normal-appearing tissue. However, while trans-synaptic degeneration is biologically plausible in MS, and supported by indirect evidence (Rocca et al., 2013; Gabilondo et al., 2014), the “real time” documentation of trans-synaptic degeneration has been challenging. Pathological studies of MS are typically not suitable for assessing trans-synaptic changes, since post-mortem studies can only assess a single pathological timepoint, and post-mortem samples of MS brains are usually acquired from older patients – often years after the phase of the disease involving overt inflammatory activity. Furthermore, radiological capturing of trans-synaptic degeneration in vivo has been a major challenge due to the limitations of imaging technology and the complex synaptically-connected central nervous system networks which can be affected by many MS lesions.Figure 1: Functionally-eloquent organization of the afferent visual pathway.The afferent visual pathway is a sensory pathway comprised of three neurons. The 1st order neurons are the shortest neurons in the pathway and are entirely unmyelinated. The cell bodies of the 1st order neurons lie in the retinal inner nuclear layer (INL), with the axons traveling to the retinal ganglion cell layer (GCL) where they synapse with the cell bodies of the 2nd order neurons. In the top row of images, the INL and GCL are highlighted here on a spectral domain optical coherence tomography image of a healthy retina (Spectralis HD-OCT, Heidelberg, Germany). The axons of the 2nd order neuron pass through the peripapillary retinal nerve fiber layer and coalesce to make up the optic nerve, becoming myelinated after they pass through lamina cribrosa. As illustrated in the second row of images, axons from the nasal half of the retina are organized within the optic nerve and cross over to the contralateral cerebral hemisphere at the optic chiasm, while axons from the temporal half of the retina remain uncrossed and continue their path within the ipsilateral cerebral hemisphere. After traversing the optic tracts, the axons of the 2nd order neurons synapse with the cell bodies of the 3rd order neurons in the lateral geniculate nucleus of the thalamus, with each thalamus receiving signals from the right and left eye, due to the crossed and uncrossed nature of the pathway. The axons of the 3rd order neurons then travel within the optic radiations to reach the primary visual cortex of the occipital lobe. From: https://collections.lib.utah.edu/ark:/87278/s6ty03rf.Figure 2: Neuroaxonal degeneration in the afferent visual pathway following axonal injury.This figure illustrates the potential patterns of neuroaxonal degeneration that may occur after injury to an axon in the afferent visual pathway (e.g., with optic neuritis), or in other synaptically-connected pathways. Following axonal injury, the affected neuron may degenerate in both an anterograde (“dying forward”) or retrograde (“dying back”) direction. Following degeneration of the injured neuron, neurodegeneration may proceed trans-synaptically to the other neurons in the chain, again in an anterograde or retrograde direction, resulting in loss of distant uninjured but synaptically-connected neurons. From: https://collections.lib.utah.edu/ark:/87278/s6ty03rf.The visual pathway is frequently probed in the examination of neurodegenerative processes in MS, and episodes of acute optic neuritis (AON) represent opportune circumstances for t