ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation

We previously generated a mouse model with a mutation in the murine Atm gen e that recapitulates many aspects of the childhood neurodegenerative diseas e ataxia-telangiectasia. Atm-deficient (Atm-/-) mice show neurological defe cts detected by motor function tests including the rota-rod, open-field tes ts and hindpaw footprint analysis. However, no gross histological abnormali ties have been observed consistently in the cerebellum of any line of Atm-/ - mice analyzed in most laboratories, Therefore, it may be that the neurolo gic dysfunction found in these animals is associated with predegenerative l esions. We performed a detailed analysis of the cerebellar morphology in tw o independently generated lines of Atm-/- mice to determine whether there w as evidence of neuronal abnormality, We found a significant increase in the number of lysosomes in Atm-/- mice in the absence of any detectable signs of neuronal degeneration or other ultrastructural anomalies. In addition, w e found that the ATM protein is predominantly cytoplasmic in Purkinje cells and other neurons, in contrast to the nuclear localization of ATM protein observed in cultured cells, The cytoplasmic localization of ATM in Purkinje cells is similar to that found in human cerebellum, These findings suggest that ATM may be important as a cytoplasmic protein in neurons and that its absence leads to abnormalities of cytoplasmic organelles reflected as an i ncrease in lysosomal numbers.