The singular qualities of motor neurones in health and disease
Version of Record online: 11 DEC 2013
© 2014 Anatomical Society
Journal of Anatomy
Special Issue: Motor Neurones and Diseases of Motor Neurones
Volume 224, Issue 1, pages 1–2, January 2014
How to Cite
Parson, S. H. (2014), The singular qualities of motor neurones in health and disease. Journal of Anatomy, 224: 1–2. doi: 10.1111/joa.12110
- Issue online: 11 DEC 2013
- Version of Record online: 11 DEC 2013
Neurones are unusual cells, with multiple and often extremely long cytoplasmic protrusions which make up their dendrites and axons. Motor neurones occur at one extreme when it comes to the number of inputs, length of the axon and the size of the peripheral contacts which are made. Motor neurones have extensive dendritic trees with synaptic inputs present throughout. Axons can be well over 1 m in length, meaning that even accounting for the large size of motor neurone cell bodies, that axoplasmic volume may exceed that of the cell body by more than tenfold. Finally, the number of peripheral connections with skeletal muscle fibres, the motor unit, can be in the order of several thousand. These facts coupled with the energy demands placed upon motor neurones during activity are often taken as reasons underpinning the apparent vulnerability of motor neurones to disease.
A very recent study has put the cost of brain disorders in the UK at a level of €134 billion per annum (Fineberg et al., 2013) and of this neuromuscular disorders are the single most expensive at €42 000 per subject, with €15 000 of this being attributed to direct costs. The status of some of these who are essentially marooned within themselves following the progression of motor neurone diseases is almost unimaginable and it is beholden upon us in the research community to continue to strive to further our understanding of motor neurones and the diseases which affect them. Therefore, in 2012 a meeting was held to bring together experts both in the basic biology of motor neurones and in the diseases which affect them at the Royal College of Surgeons of Edinburgh. The following special edition brings together reports from many of the key participants at that meeting.
There are several key themes to the material encompassed by this issue; the first is the importance of understanding motor neuronal connectivity. Beginning with inputs onto motor neurones and a clear account of the nature and roles of C boutons, the often ignored but essential intrinsic neuromodulators of motor neuronal excitability and therefore activity (Witts et al. 2014; in this issue, pp. 52–60). These large cholinergic synapses were first described in the late 1960's but their key roles are only now being elucidated. Their relatively recent implication in the aetiology of amyotrophic lateral sclerosis (ALS) has lent greater significance to their continued study. Although inputs onto motor neurones modulate their activity, ultimately the motor nerve terminal is the site of muscle activation. This neuromuscular junction (NMJ) is one of the most well studied synapses and has been used to model many synaptopathies. Ruiz and Tabares ( 2014; in this issue, pp. 74–84) show that there are very subtle but specific abnormalities in neurotransmission at the NMJ of mouse models of Spinal Muscular Atrophy (SMA), the most common, heritable form of motor neurone disease affecting children. Here they show that when levels of the SMN protein, which govern the severity of the disease are slightly reduced, that small but significant defects in neurotransmission occur, though excitation-contraction coupling is maintained probably due to the high safety factor of the NMJ. This research perhaps provides a clue to the underlying nature of many motor neurone pathologies, where steadily increasing cellular defects go unnoticed until a certain functional threshold is reached. A theme commented on in a thought-provoking piece on cellular verses system failure in ALS (Talbot 2014; in this issue, pp. 45–51), where the apparent dichotomy in the clinical presentation of ALS, focal and spreading to adjacent anatomical segments is contrasted to cell-specific vulnerability models of the disease.
The motor nerve terminal has often been viewed as a potential cause, route or trigger for cell-specific motor neuronal vulnerability, given its peripheral location outwith the central nervous system and within skeletal muscle. One mechanism for this is clearly demonstrated by the uptake and retrograde transport of noxious agents such as autoantibodies, toxins and viruses (Fewou et al. 2014; in this issue, pp. 36–44). We have amassed a great deal of information regarding toxin and viral uptake and indeed this is now used experimentally to label and transmit targeted agents to motor neurones. Much less is understood about the functional consequence of uptake of autoantibodies such as those generated in Guillain Barré syndrome where autoantobodies against acetylcholine receptors are generated. A much more rare form of autoimmunity is where antibodies are raised against muscle specific kinase (MuSK) a key mediator of activity-dependent clustering of acetylcholine receptors at the NMJ. Intriguingly it appears that rather than a complement-mediated attack on nerve terminals, the myasthenic symptoms appear to result from effects of the autoantibodies on retrograde transport in the motor axon (Koneczny et al. 2014; in this issue, pp. 29–35). These twin concepts of axonal transport and local regulation of proteins also appears to be at the root of other motor neurone disorders, for example, in both progressive motor neuropathy (PMN) and SMA where axonal signalling defects are described (Jablonka et al. 2014; in this issue, pp. 3–14).
It has long been understood that inhibitory molecules could form an important signalling cascade in the formation and maintenance of the NMJ. This study shows that neurotrophic factors local to the NMJ can modulate nerve terminal and axonal cytoskeletal dynamics by affecting local protein synthesis. Another intriguing mechanism for the action of local factors is the range of activities including modulation of neurotransmission and synapse elimination now attributed to the ever increasing family of protein kinase C (PKC) identified at the NMJ (Lanuza et al. 2014; in this issue, pp. 61–73).
A second theme for scientists and clinicians alike is the appreciation that ‘motor neurone diseases’ may not in fact be specific to motor neurones. These cells may be specifically vulnerable, or the effects on them may be specifically noticeable in terms of functional loss, but many other cell types both within and outwith the nervous system are now demonstrably affected. This is particularly apparent in SMA, where beginning with cardiovascular defects and now including organs of the digestive and respiratory systems, specific and often pre-symptomatic defects in both animal models and patients are increasingly described (Shababi et al. 2014; in this issue, pp. 15–28). Importantly, these do not appear to be a consequence of the motor pathology. An increased appreciation and understanding of these non-motor defects, something also seen in ALS where frontotemporal dementia (FTD) is an increasingly observed co-morbidity (Talbot 2014; in this issue, pp. 45-51), can only help us to understand disease pathology. Perhaps we should consider these as systemic but motor neurone-presenting diseases and focus less upon therapies targeted exclusively to motor neurones? As described in this special issue, motor neurones by virtue of their size, connectivity and activity are susceptible to a variety of insults both intrinsic and extrinsic. These are compensated for at a cellular level not least by the margin of the safety factor of the NMJ, and at a system level by behavioural and central motor adaptability. Only when a critical cellular or functional threshold is passed do symptoms become apparent, which then often progress rapidly. It is only through an increased understanding of the pre-symptomatic, cellular processes involved, that we can hope to conquer this disparate group of conditions which affect motor neurones.
This special issue is dedicated to my former PhD student: Dr R.L. ‘Becki’ Baxter, 1982–2013.