Currently we test and support the following browsers:
Please note that this is not intended to be an exhaustive list of browsers that support web standards, nor a test of browser compliance, nor a side-by-side comparison of various manufacturers’ browsers.
A major focus of our studies is investigating the molecular basis for neurodegeneration in the childhood syndrome ataxia telangiectasia (A-T). This syndrome results from dysfunction of ATM, a serine-threonine kinase and a central signal transducer of DNA damage, particularly DNA double strand breaks (DSBs). An initial key observation was the finding that the loss of ATM led to resistance to DNA damage-induced cell death in immature neural cells [Science 280:1089-1091, 1998; Genes & Development 14, 2576-80, 2000]. This was unexpected as A-T is linked to radiosensitivity, and led to our the hypothesis that a key function of ATM in the nervous system is to promote the elimination of genomically damaged immature neurons. Therefore, in its absence, the inappropriate incorporation of these damaged cells leads to their loss at later stages resulting in neurodegeneration. An important regulator of ATM is the MRN complex (so named because of its individual components Mre11, Rad50 and Nbs1) and defects in this complex can lead to diseases with similarity to A-T, including Nijmegen Breakage Syndrome (NBS; from hypomorphic mutations of NBS1) and A-T like disease (ATLD; from hypomorphic mutations of Mre11). However, notable differences are present in the neuropathological presentation of these diseases as NBS is characterized by microcephaly, while ATLD is characterized by neurodegeneration. It is unclear how defects in this complex give rise to different neurological phenotypes. Recently, we provided molecular insights into how MRN mutations lead to different neuropathology [Genes & Development, 23: 171-180, 2009]. We found that while defects in either Mre11 or Nbs1 compromised Atm activation, Mre11 mutations found in ATLD resulted in a failure to activate apoptosis after DNA damage similar to our findings in Atm-/- mice. In contrast, although Nbs1 hypomorphic mutations were defective in promoting Atm phosphorylation after DNA damage, they nonetheless induced apoptosis in a manner similar to normal brain tissue. Thus, the different DNA damage signaling arising from mutations in Mre11 or NBS1 provides a molecular basis for the different neuropathology in these related diseases. Ongoing work deals with understanding the specific DNA lesions that activate ATM signaling.