Problems in DNA Repair Linked to Two Childhood Neurodegenerative Diseases

Researchers led by Peter McKinnon from St. Jude Children’s Research Hospital have discovered a previously unknown player in two devastating rare childhood neurodegenerative diseases, ataxia telangiectasia (A-T) and spinocerebellar ataxia with axonal neuropathy 1(SCAN1). Topoisomerase 1 cleavage complex (Top1cc), which normally creates reversible breaks in DNA to enable it to unwind for cell division or transcription, accumulates in neurons of both A-T and SCAN1, and is surprisingly a common mediator of DNA damage. It was previously known that A-T is caused by a mutation in Atm, while SCAN1 is caused by a mutation in Tdp1, and the disease mechanisms were not thought to be related. This work, published online May 4, 2014 in Nature Neuroscience, reveals that these two proteins work coordinately to repair breaks in DNA, and when either is absent, levels of Top1cc increase dramatically, leading to DNA damages and ultimately to neuronal apoptosis. Impairments in DNA repair mechanisms have also been linked to ALS and adult onset neurodegenerative diseases (see February 2013 Conference News). Click here to read more.

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