One of the big Qs about #MND #ALS is 'what causes disease heterogeneity?'. E.g. Family members inheriting the same mutation but having very different disease courses. Our recent paper with @jakeayersPhD gets us closer. journals.plos.org/plosone/articl… Here is what I mean. A thread 1/7
First, a bit of background. @jakeayersPhD discovered that #MND #ALS could be transmissible in mice. A tiny amount of spinal cord material from a sick mouse injected into the spine of otherwise healthy mice could trigger disease. 2/7 link.springer.com/article/10.100…
Meanwhile, we had been characterizing how the pathological 'shape' of a protein SOD1 could be propagated from one cell to another in cell culture. 3/7
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pnas.org/content/111/9/…
In narrowing down which part of the protein is responsible for the pathological 'shape' @LukeMcAlary noticed very few #MND #ALS causing mutations in a particular part of the protein. Maybe this part is important for converting to the diseased shape. 4/7
Our work with Prof Neil Cashman had shows that changing one amino acid in that region (removing a tryptophan) dramatically changes the accumulation of the pathological form. 5/7 nature.com/articles/s4159…
That leads us back to our most recent paper. Injecting the diseased shape of SOD1 either with or without the tryptophan caused a different disease course. Most obvious in the second round of transmission (compared to previous work). 6/7
What we think this all means is that depending on the specific shape (strain) that is formed the disease course of #MND #ALS can be altered. Next job is to see if we can manipulate this process to slow the disease. 7/7
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