The molecular neuropathology of spinocerebellar ataxia type 23
The cerebellum (Latin for “little brain”) is a region of the brain that plays an important role in regulating the coordination, precision and timing of voluntary movements, and lets you know where your limbs are without looking. A malfunctioning cerebellum usually leads to ataxia. Patients with ataxia suffer from the inability to walk in a straight line, imbalance, and they lose control over speech and eye movements. Currently, there is no therapy available for any of the 44 subtypes of this progressive incapacitating disorder. A particular subset of nerve cells is affected in ataxia, namely the Purkinje cells. The Purkinje cells are the sole output of the cerebellum and as such incorporate signals from many cells in order to properly coordinate movement. They play a crucial role in the normal functioning of the cerebellum. We have modelled an ataxia subtype, spinocerebellar ataxia type 23 (SCA23), in mice. The mice contained the human SCA23 disease gene and reproduced the disease symptoms of patients. In order to determine how these symptoms arise, we studied the underlying causes in the cerebella of these mice in great detail and found that mice suffering from ataxia display small but significant changes in the cerebellar circuitry. Additionally, we observed changes in important biological routes that reduced the communication of nerve cells leading to cell death. In this thesis, we describe these changes in detail and offer a possible strategy for drug development.