Role of SOX6 in parkinsonism and neurodevelopmental disease

The symptoms of Parkinsons disease (PD) are caused by the loss of midbrain dopamine (DA) neurons. However, not all DA neurons are equally vulnerable in PD and a better understanding of the cell-type specific properties relating to selective DA neuron degeneration is needed. Most DA neurons in a midbrain region called substantia nigra (SNc) express the transcription factor SOX6. There is some evidence that SOX6 DA neurons are more vulnerable than those without in human midbrains of patients with PD. In contrast, lack of SOX6 expression may in part explain the increased resistance of DA neurons towards degeneration in another midbrain region called ventral tegmental area. But whether or how SOX6 may confer increased neuronal vulnerability remains unknown. Interestingly, human genetic variants of SOX6 have recently been discovered and cause impaired or abrogated SOX6 function resulting in neurodevelopmental disorders in affected patients including parkinsonism. Together, this suggests that SOX6 could play a pivotal role in DA neuron function, and that both, its expression as well as loss-of-function can increase the risk for neurological diseases. We propose that SOX6 DA neurons are more vulnerable to degeneration, and that this is caused among others by higher expression of specific risk genes such as those affecting DA handling and storage inside neurons. Together these may elevate the risk for oxidative damage and neuronal injury. Using mouse models of PD, biochemical, molecular biological and histological techniques complemented with human postmortem brains, we will test how SOX6 confers vulnerability to DA neurons, determine molecular alterations caused by SOX6 expression or its abrogation, and assess how SOX6 expression regulates gene expression in DA neurons.