EXPLORING THE DEVELOPING CEREBELLUM IN HUNTINGTON DISEASE (HD)

Huntington disease (HD) is an inherited neurodegenerative disease that has been studied as a condition affecting the cortex and striatum. It is caused by an abnormal expansion of a polymorphic CAG repeats in the HTT gene resulting in an abnormal polyglutamine (polyQ) expansion in the huntingtin protein.
Although the disease has a late-onset, we found that human fetuses carrying the expansion exhibit neurodevelopmental abnormalities as early as 13 weeks of gestation.
These findings are recapitulated in HD knock-in mouse embryos. Furthermore, we observed abnormal cortical circuit activity during the first postnatal week that is corrected by the second week spontaneously.
These findings, alongside the well-documented cortico-striatal degeneration led us to consider broader network disruption and search for compensatory mechanisms through connectivity that could exist long before disease manifestation.
I focused on the cerebellum as it is involved in providing sensory feedback to fine-tune motor output, and its connection with the indirect pathway in movement regulation.
I am investigating longitudinally cellular and molecular alterations in the cerebellar primordium using a mouse model of HD, focusing on the principal neurogenic zones for both excitatory and inhibitory neuronal populations. My first analysis reveals perturbations in migration, accompanied by displaced windows of maturation of both GABAergic and glutamatergic precursors. During postnatal development my preliminary findings revealed disruptions in synaptic density on the dendrite of Purkinje cells in HD.
Collectively, our data may provide insights into the potential role of the cerebellum in the brain's compensatory mechanisms during the extended pre-symptomatic phase of HD.