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Huntington Disease (HD) and certain forms of amyotrophic lateral sclerosis and dementia (ALS/FTD) are inherited. Their genetic root cause is the expansion of short, repeated stretches of DNA, namely CAG in the huntingtin gene for HD and GGGGCC (G4C2) repeats in the C9orf72 gene for ALS/FTD. These inherited expansions continue to expand during life fueling disease manifestation and progression. Our project aims (1) to measure the size of the expansion accurately at the level of single cells, contrasting affected and unaffected parts of the body and the brain, (2) to identify at what time points in life and in which cells these expansions take place, (3) to understand the how expansion comes about and through what cellular machinery the size of the expansion is modified, (4) to understand what consequences a change in repeat size has for a cell by looking in an unbiased fashion at alterations of gene expression and at gene mutations, and (5) to demonstrate the impact of interfering with repeat sizes. These studies will be carried out in model systems such as mice and yeast genetically altered in such a way that the genetic change at the root of the human disorder is mimicked as good as feasible and then validated in cells derived from patients affected by the respective disorders as well brain tissues donated by patients. Ultimately, suppression of expansion should be beneficial for patients by slowing progression; reductions in expansion size could even be curative. To achieve these ambitious goals, we have brought together European and Canadian leaders in the field.