Motor Neuron Disease (MND; also known as Amyotrophic Lateral Sclerosis) is a group of rare, though fatal, neurodegenerative disorders that have affect around 222,000 people worldwide (Arthur et al., 2016). The progression of the disease is rapid, with most patients surviving just 2-4 years post-diagnosis (Rothstein, 2009). Most deaths are caused by respiratory failure.
There is no simple diagnostic test for MND. Initial symptoms include slurred speech (dysarthria), difficulty in executing movements due to muscle weakness, “foot drop” where the sufferer cannot keep their feet at a right angle and weakened grip (Hobson and McDermott, 2016). These are all caused by muscle atrophy. Often the symptoms will unilaterally affect one side of the body and spread as the disease progresses. Though the condition is debilitating, patients are rarely in physical pain.
Additionally, around 15% of those presenting with MND also have frontotemporal dementia (Ferrari et al., 2013). The latter causes cognitive and behavioural dysfunction, often co-occurring with non-fluent aphasia (or inability to correctly use language). It is caused by a severe and dramatic loss of neurons in the frontal and temporal regions of the brain. In around 40% of cases, neuronal death is caused by an accumulation of misfolded TAU – a protein that has also been implicated in Alzheimer’s disease. Tau pathology is not a common hallmark of ALS, though it has been found that ubiquitin inclusions are associated with cases of co-morbidity of FTD-ALS.
The vast majority of MND cases are idiopathic, occurring seemingly at random in the population (Kiernan et al, 2011). Nevertheless, some correlations have been made between environmental factors and incidence of the disease. One report found that severe electrical shock can lead to MND (Jafari, Couratier and Camu, 2001), whilst others found that head trauma causes an eleven-fold increase in relative risk (Chen et al., 2007). Despite these correlations, it is unlikely that there is a one-to-one association between any environmental factor and development of MND. Instead, many lifestyle and biological factors are likely to interact.
Inherited MND is rare, though it still accounts for around 10% of cases (Maruyama et al., 2010). Mutations in SOD1, which encodes a superoxide dismutase, accounts for around 20% of familial MND cases, though it has also been implicated in around 5% of seemingly sporadic cases. Normally, SOD1 converts potentially harmful superoxide radicals in the mitochondria to less dangerous molecules. Mutations in the gene cause a gain-of-function phenotype, and though the exact molecular mechanism is unknown, it appears to promote selectively promote apoptosis in the mitochondria of the spinal cord (Pasinelli et al., 2004). Two theories have been suggested: one proposes that the molecular mechanisms regulating SOD1 are ineffective at increased doses of the protein. Similarly, the second theory proposes that the increased levels of protein means that more misfolded protein deposits in the outer mitochondrial membrane, causes apoptosis (Tafuri et al., 2015). The two theories overlap, though neither fully explain why SOD1 toxicity is specific to spinal cord neurons.
TDP-43 (also called TAR-DNA Binding Protein, TARDBP) also has strong association with familial MND, particularly those that co-occurr with frontotemporal dementia (Ferrari et al., 2013). Its protein product regulates the transcription of CFTR, binding to intron/exon junctions to regulate different splice variants, though other genomic regulatory roles have also been established (Sephton et al., 2011). TDP-43 is usually localised to the nucleus, though it can form aggregates and cause nuclear depletion (Xu, 2012). This appears to be associated with neurodegenerative diseases such as MND, though the exact pathological mechanisms are unknown.
Whilst much basic research is being done into the underlying cause of the disease, many are focusing research efforts on finding treatments and, hopefully, cures for those already affected by the condition. By convention, patients are prescribed a mixture of physiotherapy and medication to alleviate pain.
Riluzole is a sodium channel inhibitor, and thus far is the only approved medication shown to delay the onset of advanced MND symptoms. Case-control studies show that when prescribed to those aged over seventy, riluzole increases survival rate by 30% over a twelve-month period (Zoccolella et al., 2007). Its neuroprotective function comes from its ability to block glutamate transmission (Kretschmer, 1998). Though naturally found in the body, excess amounts of glutamate can damage neurons and has been implicated in other neurodegenerative diseases such as Parkinson’s.
Newer treatments are, of course, currently being researched. In particular, new links are being established between gut health and the development of neurodegenerative diseases. In a mouse model of MND it was found that butyrate – a natural product produced by bacteria in the colon – significantly reduced the degree of permeability of the gut (Zhang, 2017). Such intestinal damage is characteristic of MND and results in severe chronic inflammation. Mice receiving the treatment both had less leakage from the intestine and had longer life expectancy.
There are other lifestyle factors that may alter the progression of the motor symptoms associated with MND. Many patients will experience a dramatic loss in weight and muscle mass, both as a direct consequence of muscle degradation but also as an indirect consequence of being unable to swallow or chew. Previous evidence indicated that those who were obese when diagnosed had a higher survival rate: thus, researchers wanted to investigate whether feeding patients a high-calories diet could achieve similar effects (Wills et al., 2014). Those on the high-calorie diet appeared to suffer from fewer adverse symptoms than those in the control group, and the study has now progressed to a large-scale trial to see if the results are reproducible.
Progress on developing a cure is regrettably slow: for the vast majority of those currently living with MND, the only real options are treatments that either relieve pain or extend life by a few months. Some suggest that with the advent of genome-editing technologies such as CRISPR-Cas9, the familial form of MND could be eliminated completely – though this, of course, comes along with its own set of ethical issues. Nevertheless, there is significant hope that with increased understanding of the disease, MND will eventually be cured.
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