Abstract
BackgroundProteolysis of huntingtin (Htt) plays a key role in the pathogenesis of Huntington's disease (HD). However, the environmental cues and signaling pathways that regulate Htt proteolysis are poorly understood. One stimulus may be the DNA damage that accumulates in neurons over time, and the subsequent activation of signaling pathways such as those regulated by IκB kinase (IKK), which can influence neurodegeneration in HD.Methodology/Principal FindingsWe asked whether DNA damage induces the proteolysis of Htt and if activation of IKK plays a role. We report that treatment of neurons with the DNA damaging agent etoposide or γ-irradiation promotes cleavage of wild type (WT) and mutant Htt, generating N-terminal fragments of 80–90 kDa. This event requires IKKβ and is suppressed by IKKα. Elevated levels of IKKα, or inhibition of IKKβ expression by a specific small hairpin RNA (shRNA) or its activity by sodium salicylate, prevents Htt proteolysis and increases neuronal resistance to DNA damage. Moreover, IKKβ phosphorylates the anti-apoptotic protein Bcl-xL, a modification known to reduce Bcl-xL levels, and activates caspases that can cleave Htt. When IKKβ expression is blocked, etoposide treatment does not decrease Bcl-xL and activation of caspases is diminished. Similar to silencing of IKKβ, increasing the level of Bcl-xL in neurons prevents etoposide-induced caspase activation and Htt proteolysis.Conclusions/SignificanceThese results indicate that DNA damage triggers cleavage of Htt and identify IKKβ as a prominent regulator. Moreover, IKKβ-dependent reduction of Bcl-xL is important in this process. Thus, inhibition of IKKβ may promote neuronal survival in HD as well as other DNA damage-induced neurodegenerative disorders.
Highlights
Huntington’s disease is a neurodegenerative disorder caused by expansion of a CAG repeat, which is translated into a polyglutamine stretch in the N-terminus of Htt protein [1]
The novel aspects of present work are the triggering of Htt proteolysis by DNA damage and the identification of IKKb as a prominent regulator of enzymes known to cleave Htt
Our data support a protective role for IKKa, whose expression in neurons prevents DNA damage-induced Htt proteolysis (Fig. 8)
Summary
Huntington’s disease is a neurodegenerative disorder caused by expansion of a CAG repeat, which is translated into a polyglutamine (polyQ) stretch in the N-terminus of Htt protein [1]. Elevated expression of HMGBs protects against polyQ-induced neurotoxicity in primary neurons and in a Drosophila polyQ model [15]. DNA damage induced by oxidative stress is an important factor in the development of neurotoxicity and phenotypic changes in a chemical model of HD [16]. One contributing factor may be the DNA damage-induced activation of p53 and IKK signaling pathways, which have been implicated in HD neurotoxicity [14,17,18]. The environmental cues and signaling pathways that regulate Htt proteolysis are poorly understood. One stimulus may be the DNA damage that accumulates in neurons over time, and the subsequent activation of signaling pathways such as those regulated by IkB kinase (IKK), which can influence neurodegeneration in HD
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