Publication date: Feb 06, 2020
A new publication used tiny 3D brain models created from human cells to show that the mutation that causes HD could lead to early changes in brain development. So let’s put these findings into context and dig into what these developmental changes that have been discovered using human cells in a dish might mean for HD patients. Getting human brain cells without collecting brain samplesEven though HD is unique to humans, most organisms have a version of the gene that is mutated to cause HD – huntingtin, or Htt for short. If scientists are interested in studying a brain disease like HD, they can then turn those iPSCs into the cell types of interest, like neurons. And even better, if the skin or blood cells are from an HD patient, scientists then have everything they need to study the neurons of that patient without having to take a brain sample. You are a beautiful and unique snowflakeIn a recent study, these brain organoids were used to investigate the impact that the mutation that causes HD has on their development. If researchers take cells from 2 people, one with HD and one without, their cells will not only contain the different CAG lengths of that person’s HTT gene, but will also contain all the other genetic differences that make them uniquely them! So back to those identically different cells – to prevent any confusion in their study about whether the results are from different CAG lengths in the HD gene or some other unique DNA code a person has, researchers used a series of cell lines originating from a single cell line that has been genetically altered only within the HTT gene so that it contains CAG repeats of different sizes. In this case, the CAG repeat tract was increased from 30 (to represent someone without a risk for HD) to 45, 65, or 81 (representing adult-, adolescent-, or juvenile-onset HD, respectively) while all other genes in these cells remained identical. Pretty clever!Early-onset juvenile HD may not be a purely degenerative disorderWhen using all 4 cell lines to create organoids, the first thing the researchers noticed was that even though organoids from all 4 lines were the same size, the HD organoids developed smaller internal structures that developmentally lead to the formation of important brain cells called neurons, suggesting that brain development is blunted. Even though the 2 studies found opposite effects in the speed of HD organoid neurodevelopment, each study was performed slightly differently, using different cell lines and measuring effects at different time points. So you can think of this study like an unfinished book at the moment – we’ll have to tune back in after its final publication to get the full story. Do these developmental changes ever normalize?While the organoids are very cool because they can tell us about HD-related changes at the cellular level that occur early in development using human cells, we really need data from patients to interpret the effect that any changes may or may not have on a fully developed human. Another study did just that and examined the sizes of different brain structures of children and adolescents (age 6 to 18) with and without the adult-onset form of the HD mutation using MRI.