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

Abstract

We previously generated a mouse model with a mutation in the murine Atm gene that recapitulates many aspects of the childhood neurodegenerative disease ataxia-telangiectasia. Atm-deficient (Atm؊͞؊) mice show neurological defects detected by motor function tests including the rota-rod, open-field tests and hindpaw footprint analysis. However, no gross histological abnormalities have been observed consistently in the cerebellum of any line of Atm؊͞؊ mice analyzed in most laboratories. Therefore, it may be that the neurologic dysfunction found in these animals is associated with predegenerative lesions. We performed a detailed analysis of the cerebellar morphology in two independently generated lines of Atm؊͞؊ mice to determine whether there was 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, we 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 increase in lysosomal numbers.

Phosphatidylinositol-4-Kinase Type II α Is a Component of Adaptor Protein-3-derived Vesicles

“…This finding is consistent with an involvement of AP-3 in the targeting of membrane proteins to lysosomes. We detected the AP-3 cargo proteins LAMP 1, 2, and TI-VAMP/VAMP7 (Bonifacino and Traub, 2003;Martinez-Arca et al, 2003), an AP-3-interacting protein that regulates lysosome content (ATM) (Lim et al, 1998;Barlow et al, 2000), proteins related to pigment dilution genes (vps33b) (Stepp et al, 1997), and gene products affected in pigment dilution/HermanskyPudlak syndrome (BLOC I subunits pallid, muted, SNA-PAP, and dysbindin/sandy) (Dell'Angelica, 2004). The presence of BLOC1 in AP-3-derived vesicles provides a mechanistic explanation to the overlapping phenotypes observed in mice and humans harboring mutations in either AP-3 or BLOC I subunits (Dell'Angelica, 2004).…”

Up-Regulation of Cation-Independent Mannose 6-Phosphate Receptor and Endosomal-Lysosomal Markers in Surviving Neurons after 192-IgG-Saporin Administrations into the Adult Rat Brain

“…This is substantiated, in part, by the experimental data showing that 1) the EL system can be up-regulated in response to the repair mechanisms resulting from cumulative aging, genetic, oxidative, and chemical factors 11,49,50 ; 2) activation of the lysosomal system can restore chloroquine-induced abnormal protein deposits and synaptic decline in hippocampal slice preparation 51 ; and 3) neurons that are not susceptible to death in animal models of neurodegeneration and Alzheimer's disease pathology exhibit increased activation of the EL system. 50,52,53 However, it is of interest to note that the frontal cortex, a region less severely affected by 192-IgG-saporin treatment, showed an up-regulation of the CI-MPR but no significant alterations in Rab5 or LAMP2 as observed in the septum/DBB. Because CI-MPR can mediate multiple functions including cell signaling and internalization leading to degradation/activation of various molecules (ie, IGF-II, leukemia inhibitory factor, and latent transforming growth factor-␤), 1,2,5,6,9,10 it is likely that cortical receptors after the immunotoxin treatment may participate in other functions in addition to regulation of the EL system.…”

ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain

“…However, the question of whether the neurodegeneration observed in AT patients results from a loss of this DNA damage response function of ATM has been controversial, since several authors have found that ATM protein is located in the cytoplasm of Purkinje neurons in the human [9] and rodent [10,11] brain. Recently however, Shiloh and co-workers [12,13] found that the ATM protein is present in the nucleus of neuronal derived human cells maintained in tissue culture.…”