Figure 6.

Schematic diagram showing the consequences of genomic instability resulting from defective BER and ATM deficiency in the cerebellum leading to ataxia. The cerebellum, which is located at the back of the brain and is involved in the coordination of motor movement, comprises distinct cellular layers: the molecular layer, Purkinje layer and granule cell layer. Purkinje cell axons transmit inhibitory signals (−) to the deep cerebellar nucleus while integrating inhibitory inputs (−) from interneurons (Stellate and Basket cells) in the molecular layer and excitatory inputs (+) from Granule cells which are under the inhibitory control (−) of Golgi cells in the granule cell layer, as well as (+) inputs from the climbing fibers (not shown). As the only neuronal output is from the Purkinje cells, their dysfunction leads to abnormal coordination of movement (ataxia). Improper responses to chronic DNA damage in the cerebellum due to faulty base excision repair (BER) and ATM dysfunction likely result in various defects, including aberrant DNA methylation and consequently reduced ITPR1 expression in Purkinje cells. ITPR1 is involved in homeostatic control of Ca₂⁺ levels necessary for normal Purkinje cell function (54). This physiological condition might be one of contributing factors to cerebellar ataxia resulting from genomic instability.