Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (12): 2682-2684.doi: 10.4103/1673-5374.373661

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

Olwen C. Murphy*, Peter A. Calabresi, Shiv Saidha   

  1. Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
  • Online:2023-12-15 Published:2023-06-15
  • Contact: Olwen C. Murphy, MBBCh, MD, MRCPI, omurphy2@jhmi.edu.
  • Supported by:

    This work was funded by the National MS Society (RG-1606-08768 & RG-1907-34405 to SS), Race to Erase MS (to SS), and NIH/NINDS (R01NS082347 to PAC). 

    OCM receives funding from the Race to Erase MS Foundation.

    PAC has received consulting fees from Disarm, Nervgen, and Biogen and is Principal Investigator on grants to JHU from Biogen, Genentech, Prinicpia, and Annexon.

    SS has received consulting fees from Medical Logix for the development of CME programs in neurology and has served on scientific advisory boards for Biogen, Novartis, Genentech Corporation, TG therapeutics & Bristol Myers Squibb. He has performed consulting for Novartis, Genentech Corporation, JuneBrain LLC, and Lapix therapeutics. He is the Principal Investigator of investigator-initiated studies funded by Genentech Corporation and Biogen. He previously received support from the Race to Erase MS foundation. He has received equity compensation for consulting from JuneBrain LLC and Lapix therapeutics. He was also the site investigator of trials sponsored by MedDay Pharmaceuticals, Clene Pharmaceuticals, and is the site investigator of a trial sponsored by Novartis.
    The authors report no other potential conflicts of interest related to this manuscript.

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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.