DNA-PK and P38 MAPK: A Kinase Collusion in AlzheimerÃ¢ÂÂs Disease?Jyotshna Kanungo*
Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, USA
- *Corresponding Author:
- Jyotshna Kanungo PhD
Division of Neurotoxicology, National Center for Toxicological Research
U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA
Fax: 870- 543-7143
Received Date: April 07, 2017; Accepted Date: April 14, 2017; Published Date: April 19, 2017
Citation: Kanungo J (2017) DNA-PK and P38 MAPK: A Kinase Collusion in Alzheimer’s Disease? Brain Disord Ther 6:230. doi: 10.4172/2168-975X.1000230
Copyright: © 2017 Kanungo J. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The pathogenesis of Alzheimer’s disease (AD), characterized by prevalent neuronal death and extracellular deposit of amyloid plaques, is poorly understood. DNA lesions downstream of reduced DNA repair ability have been reported in AD brains. Neurons predominantly use a mechanism to repair double-strand DNA breaks (DSB), which is non-homologous end joining (NHEJ). NHEJ requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK is a holoenzyme comprising the p460 kD catalytic subunit (DNA-PKcs) and its activator Ku, a heterodimer of p86 and p70 subunits. Ku first binds and then recruits DNA-PKcs to double-stranded DNA ends before NHEJ process begins. Studies have shown reduced NHEJ activity as well as DNA-PKcs and Ku protein levels in AD brains suggesting possible contribution of unrepaired DSB to AD development. However, normal aging brains also show reduced DNA-PKcs and Ku levels thus challenging the notion of any direct link between NHEJ and AD. Another kinase, p38 MAPK is induced by various DNA damaging agents and DSB itself. Increased DNA damage with aging could induce p38 MAPK and its induction may be sustained when DNA repair is compromised in the brain with reduced DNA-PK activity. Combined, these two events may potentially set the stage for an awry nervous system approaching AD.