Although the length of CAG repeat expansion may highly anticorrelates with the age at onset of Huntington disease (HD), genetic modifiers may have a significant impact in HD. One class of modifiers that has recently drawn attention is DNA repair genes. Although some DNA repair genes may be associated with somatic CAG expansion, the involvement of DNA repair genes might reach far beyond that phenomenon, notably in terms of stress response and compensation. HD is marked by neurodegeneration but also has an increasingly studied neurodevelopmental component. Recent advances in stem cells technologies now allow for a comprehensive study of neurodevelopmental processes in vitro, enabling to investigate the role of stress response mechanisms such as DNA repair in the earliest phases of the HD process and test whether DNA damage and repair features established at the time of neuronal differentiation might be conserved in adult neurons.
To this end, we study DNA damage and DNA Damage Response (DDR) in human HD stem cells including an isogenic pair of patient-derived Neural Stem Cells (NSCs) and its genetically corrected counterpart differentiated in vitro from induced Pluripotent Stem Cells (iPSCs). To this end, we use markers of DNA damage levels and reporters of DDR pathway activities in response to Single Strand Breaks (SSB) and Double Strand Breaks (DSB).
We will present results on the alteration of SSB and DSB responses in human HD NSCs, discussing how understanding the specificities of DDR alterations during neuronal differentiation may shed light on disease mechanisms, seminal effects and potential therapeutic targets.