Ian Paul Johnson
Patrizia Longone- 1Anatomy and Pathology, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
- 2Molecular Neurobiology Unit, Experimental Neurology, Fondazione Santa Lucia, Rome, Italy
A commentary on
The recent paper by Tai et al. (1) is a timely reminder that age-related neurodegenerative diseases rarely exist in isolation, and that we should make every effort to use points of commonality to better understand the pathophysiology of these largely untreatable conditions. In their paper (1), the authors present two cases of amyotrophic lateral sclerosis (ALS) coexisting with myasthenia gravis (MG) and review the literature on this. They report that motoneuronal death in this rare syndrome can be preceded or followed by MG and conclude that the weight of evidence points toward a common neuromuscular defect operating in both diseases. This is important because the interdependence of motoneurones and their peripheral targets is well known. This was shown in the early studies of Hamburger (2, 3) and confirmed in more recent studies of the myotrophic and neuroprotective effect of muscle-derived molecules in experimental motoneuronal death and models of human motoneuronal diseases (4–6). Since MG is characterized by autoantibodies to the acetylcholine receptor at the neuromuscular junction (NMJ), Tai et al. (1) unsurprisingly implicate autoimmune damage at the NMJ in the pathogenesis of ALS. Further studies may show this may be the case, but we can broaden this concept to include failure of neuromuscular reciprocal interaction. This could include failure of motor axon and muscle to respond to trophic molecules due to reduced or aberrant receptor synthesis, impaired downstream signaling or axonal transport. Axon degeneration, from distal synaptic compartments, has been described as an early event in both human disease and animal models (7, 8). These observations support the “dying back” hypothesis by which the degeneration of the NMJ and associated muscle function precede the death of motor neurons and contributes to the disease process (7–9). Moreover, the notion of non-cell autonomous degeneration in ALS involves defects not just confined to the glial cells but retained by the muscle as well. ALS has been associated with alterations of energy homeostasis induced by mitochondrial muscle breakdown (10), and by trophic factors such as insulin-like growth factor-1 (IGF-1) and glial cell-derived neurotrophic factor that are secreted by skeletal muscle, and are known to stabilize the NMJ and thereby promote motoneuron survival (11, 12). A recent study of motor axonopathy induced in mice by overexpression of an inhibitory binding protein for IGF-1, led to the suggestion that a defect in well-known neurotrophic and myotrophic effects of IGF-1 might be common to both diabetic neuropathy and ALS (13). There is no doubt that disruption of the NMJ, seen as fasciculation and motor unit enlargement is an early feature of ALS (14, 15), and associations between excessive motor activity or enlarged motor units and the development of ALS have been recognized (16). Thus muscles, similarly to glial cells, can promote a vicious cycle of energy impairment and lack of trophic factor release that interacting with other systems, when set in motion, amplify their own processes and may accelerate the development of ALS.
Whether disease primarily affects muscle or motoneurones is critical to disease management, but this progression may be an endpoint that reveals little about its origins. In this regard, the paper by Tai et al. (1) prompts us to reevaluate the role of the peripheral target in neurodegenerative diseases where attention has traditionally been focused centrally.
Author Contributions
IJ wrote the initial draft. PL revised the initial draft and contributed further writing. Both the authors collected data from literature and revised the final manuscript.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1. Tai H, Cui L, Guan Y, Liu M, Li X, Huang Y, et al. Amyotrophic lateral sclerosis and myasthenia gravis overlap syndrome: a review of two cases and the associated literature. Front Neurol (2017) 8:218. doi:10.3389/fneur.2017.00218
2. Hamburger V. Regression versus peripheral control of differentiation in motor hypoplasia. Am J Anat (1958) 102:365–409. doi:10.1002/aja.1001020303
3. Hollyday M, Hamburger V. Reduction of the naturally occurring motor neuron loss by enlargement of the periphery. J Comp Neurol (1976) 170:311–20. doi:10.1002/cne.901700304
4. Gould TW, Oppenheim RW. Motor neuron trophic factors: therapeutic use in ALS? Brain Res Rev (2011) 67:1–39. doi:10.1016/j.brainresrev.2010.10.003
5. Kariya S, Obis T, Garone C, Akay T, Sera F, Iwata S, et al. Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation. J Clin Invest (2014) 124:785–800. doi:10.1172/JCI72017
6. Tovar YRLB, Ramirez-Jarquin UN, Lazo-Gomez R, Tapia R. Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy. Front Cell Neurosci (2014) 8:61. doi:10.3389/fncel.2014.00061
7. Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol (2004) 185:232–40. doi:10.1016/j.expneurol.2003.10.004
8. Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P. Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci (2000) 20:2534–42.
9. Musaró A. Understanding ALS: new therapeutic approaches. FEBS J (2013) 280:4315–22. doi:10.1111/febs.12087
10. Dupuis L, Gonzalez de Aguilar JL, Echaniz-Laguna A, Eschbach J, Rene F, Oudart H, et al. Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. PLoS One (2009) 4:e5390. doi:10.1371/journal.pone.0005390
11. Dobrowolny G, Giacinti C, Pelosi L, Nicoletti C, Winn N, Barberi L, et al. Muscle expression of a local IGF-1 isoform protects motor neurons in an ALS mouse model. J Cell Biol (2005) 168:193–9. doi:10.1083/jcb.200407021
12. Krakora D, Mulcrone P, Meyer M, Lewis C, Bernau K, Gowing G, et al. Synergistic effects of GDNF and VEGF on lifespan and disease progression in a familial ALS rat model. Mol Ther (2013) 21:1602–10. doi:10.1038/mt.2013.108
13. Rauskolb S, Dombert B, Sendtner M. Insulin-like growth factor 1 in diabetic neuropathy and amyotrophic lateral sclerosis. Neurobiol Dis (2017) 97:103–13. doi:10.1016/j.nbd.2016.04.007
14. de Carvalho M, Kiernan MC, Swash M. Fasciculation in amyotrophic lateral sclerosis: origin and pathophysiological relevance. J Neurol Neurosurg Psychiatry (2017). doi:10.1136/jnnp-2017-315574
15. Dharmadasa T, Henderson RD, Talman PS, Macdonell RA, Mathers S, Schultz DW, et al. Motor neurone disease: progress and challenges. Med J Aust (2017) 206:357–62. doi:10.5694/mja16.01063
Keywords: amyotrophic lateral sclerosis, myasthenia overlap syndrome, neuromuscular junction, neurotrophic support, “dying back” hypothesis
Citation: Johnson IP and Longone P (2017) Commentary: Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Review of Two Cases and the Associated Literature. Front. Neurol. 8:356. doi: 10.3389/fneur.2017.00356
Received: 08 June 2017; Accepted: 06 July 2017;
Published: 27 July 2017
Edited by:
Stefano L. Sensi, Università degli Studi “G. d’Annunzio” Chieti – Pescara, ItalyReviewed by:
Nicola B. Mercuri, University of Rome Tor Vergata, ItalyValerio Frazzini, Università degli Studi dell’Aquila, Italy
Copyright: © 2017 Johnson and Longone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ian Paul Johnson, aWFuLmpvaG5zb25AYWRlbGFpZGUuZWR1LmF1;
Patrizia Longone, cC5sb25nb25lQGhzYW50YWx1Y2lhLml0