DNA-PK and P38 MAPK: A Kinase Collusion in Alzheimer's Disease?

Abstract

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-PK_cs) and its activator Ku, a heterodimer of p86 and p70 subunits. Ku first binds and then recruits DNA-PK_cs to double-stranded DNA ends before NHEJ process begins. Studies have shown reduced NHEJ activity as well as DNA-PK_cs and Ku protein levels in AD brains suggesting possible contribution of unrepaired DSB to AD development. However, normal aging brains also show reduced DNA-PK_cs 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.

Keywords: Amyloid beta; DNA repair; Ku; NHEJ; ROS.

Figure 1

Schematic presentation of a potential link of DNA double strand breaks (DSB), DNA-PK and p38α MAPK in normal and AD brains. Upon induction of DSBs either by normal aging/ROS or other DNA damaging agents, Ku80/Ku70 andDNA-PK_cs and are rapidly recruited to DNA ends, and DNA repair occurs as it would in normal brains. However, in AD brains, in addition to formation of Aβ oligomers from Aβ peptides, sustained DSBs in the genome would cause genome instability leading to the loss of normal neuronal activity. Additionally, with depleted DNA-PK activity andNHEJ, sustained DSBs could activate p38α MAPK via ATM triggering neuronal death, potentially mediated by one of the downstream pathways being ERK MAPK down regulation and another via c-jun activation. Disruption of somatostatin signaling via Ku80 (a somatostatin receptor) depletion may also lead to Aβ oligomerization, a prime trigger of AD. Shaded areas show normal (gray) and deregulated sequences of events (purple).