METABOLIC DYSFUNCTIONS MAY BE CAUSING SELECTIVE ANTERIOR PURKINJE CELL LOSS IN THE CEREBELLUM OF A CHRISTIANSON SYNDROME MOUSE MODEL

Christianson Syndrome is an incurable neurological disorder where ataxia is one of the most debilitating symptoms. In the cerebellum of Christianson Syndrome patients, an intriguing cell death pattern is seen. The primary output neurons, Purkinje cells, exhibit selective vulnerability in the anterior, while those in the posterior region remain resilient, despite being exposed to the same genetic insult. What could be causing this patterned cell death? Anterior Purkinje cells fire at a higher frequency and have a higher energy demand than those in the posterior, suggesting energy-related issues may underlie this selective cell death. Energy imbalances are often caused by metabolic dysfunctions, which are increasingly being recognized as a factor in many neurodegenerative disorders, including ataxias. Therefore, we hypothesized that metabolic dysfunctions are causing this selective anterior Purkinje cell vulnerability. Using a multidisciplinary approach, we found a significant reduction in the essential protein Hypoxanthine-guanine phosphoribosyltransferase involved in the generation of purines, essential precursors for ATP, the energy currency of the cell. We also found that mitochondria, the major producers of ATP, had damaged cristae and were reduced in number only in the vulnerable anterior at the onset of ataxia (P60). Our findings therefore suggest that improper energy metabolism may contribute to cell death in Christianson Syndrome ataxia and could be a potential therapeutic target.