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Deregulated Cdk5 promotes oxidative stress and mitochondrial dysfunction
Author(s) -
Sun KaiHui,
De Pablo Yolanda,
Vincent Fabien,
Shah Kavita
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05616.x
Subject(s) - cyclin dependent kinase 5 , oxidative stress , neurodegeneration , programmed cell death , microbiology and biotechnology , reactive oxygen species , mitochondrion , mitochondrial ros , biology , apoptosis , kinase , biochemistry , protein kinase a , medicine , disease , cyclin dependent kinase 2
Oxidative stress is one of the earliest events in Alzheimer’s disease (AD). A chemical genetic screen revealed that deregulated cyclin‐dependent kinase 5 (Cdk5) may cause oxidative stress by compromising the cellular anti‐oxidant defense system. Using novel Cdk5 modulators, we show the mechanism by which Cdk5 can induce oxidative stress in the disease’s early stage and cell death in the late stage. Cdk5 dysregulation upon neurotoxic insults results in reactive oxygen species (ROS) accumulation in neuronal cells because of the inactivation of peroxiredoxin I and II. Sole temporal activation of Cdk5 also increases ROS, suggesting its major role in this process. Cdk5 inhibition rescues mitochondrial damage upon neurotoxic insults, thereby revealing Cdk5 as an upstream regulator of mitochondrial dysfunction. As mitochondrial damage results in elevated ROS and Ca 2+ levels, both of which activate Cdk5, we propose that a feedback loop occurs in late stage of AD and leads to cell death (active Cdk5 → ROS → excess ROS → mitochondrial damage → ROS → hyperactive Cdk5 → severe oxidative stress and cell injury → cell death). Cdk5 inhibition upon neurotoxic insult prevents cell death significantly, supporting this hypothesis. As oxidative stress and mitochondrial dysfunction play pivotal roles in promoting neurodegeneration, Cdk5 could be a viable therapeutic target for AD.