Love them or loath them, the band Steps’ first single ‘5,6,7,8’ was a techno line dance song released in 1998 from their debut album ‘step one’, with the B side ‘words of wisdom’.
Using this forced and purely tenuous link and an equally awkward segue, I would like to share with you the news that the journal Neurology this week published further words of wisdom from Professor Adriano Chio, Professor Ammar Al-Chalabi and colleagues, that revisits the multistep hypothesis of MND. Their previous work showed that when no genetic cause is considered, developing MND is a six-step process. In their most recent work, the team investigated how many of the steps does a genetic mutation account for in this multistep process, with a focus on the most common MND causative genes SOD1, TARDBP, and C9ORF72.
Although clues to the basic biology of MND are being uncovered by some of the best and brightest scientists of their generation, the underlying causes of this devastating disease remain undefined. One of the most studied contributing factors to date is the involvement of genetics, with over 20 causative genes identified so far. These are most often found in about 5-10% of all cases of MND in which family history of the disease has been found. In these people, a change in a gene makes a defective protein, which causes predisposition to the disease. In some families the disease occurs in several members and is passed through the family via the inherited gene mistake.
However, carrying one of the causative genes does not necessarily lead to the development of MND, as there are other environmental and lifestyle components involved. And while a great number of studies identified some of these, there is still a pressing need to understand them further in order to know exactly how they are involved in the development of MND.
What is the multistep hypothesis of MND?
According to the multistep hypothesis (Lancet Neurology, 2014), there are six steps that lead to the development of MND – that is, six factors associated with MND causation. And while this is a great progress towards understanding the cause of MND, these steps can occur in any order and be of a potentially infinite combination of yet unknown factors, making their identification incredibly difficult. But since we know that some of these factors must be genetic, looking into the number of steps in people with a known genetic mutation could help us narrow down the selection, and identify some of the other factors.
Looking at people with a known genetic mistake, the authors tested the theory that a gene mutation may account for one or more of the six steps towards developing MND. They looked at data of 1,077 people with MND taken from patient registries in Italy and the Republic of Ireland, out of which 109 had an identified mutation in either SOD1 (20), C9ORF72 (74), or TARDBP (15) gene.
Analysis of all the 1,077 cases using the previously tested mathematical model confirmed the six-step process across all forms of MND. When each gene was considered separately however, the results for people with a genetic mutation were different to those without. They still indicated a multistep process, although this time with a reduced number of steps for each gene, indicating that each mutation adds to the chance of developing MND with a different, and significant, amount. Specifically, the number of steps is reduced from six steps (where no genetic mutation is present) to four steps in TARDBP, three steps in C9orf72, and two steps in SOD1.
So why is this such a significant and useful finding? Having this knowledge may change our approach to how we search for environmental and other factors; we are more likely to identify risk factors when we are only looking for one additional step that triggers the disease (as is the case in people with the SOD1 mutation) than in people with no known gene mutation, where searching for the six steps would be more like searching for a needle in a haystack – you would quite likely need to make sure to find all six needles in the right order and at the right time.
The hunt is now on for what the MND steps might represent. This could either be individual environmental or lifestyle factors (e.g., pesticide exposure, smoking, or increased physical activity) or an accumulation of these factors causing faulty cellular processes (e.g., mitochondrial dysfunction or oxidative stress) where each of these could be that one specific step. But however hard this search might be, it has just been made a whole lot easier by the extension of the multistep hypothesis of MND.