Oxidative stress mediates tau-induced neurodegeneration in Drosophila

Abstract

Markers of oxidative damage have been detected in brain tissue from patients with Alzheimer disease (AD) and other neurodegenerative disorders. These findings implicate oxidative injury in the neurodegenerative process, but whether oxidative stress is a cause or a consequence of neurotoxicity remains unclear. We used a Drosophila model of human tauopathies to investigate the role of oxidative stress in neurodegeneration. Genetic and pharmacological manipulation of antioxidant defense mechanisms significantly modified neurodegeneration in our model, suggesting that oxidative stress plays a causal role in neurotoxicity. We demonstrate that the JNK signaling pathway is activated in our model, which is in agreement with previous findings in AD tissue. Furthermore, we show that the extent of JNK activation correlates with the degree of tau-induced neurodegeneration. Finally, our findings suggest that oxidative stress acts not to promote tau phosphorylation, but to enhance tau-induced cell cycle activation. In summary, our study identifies oxidative stress as a causal factor in tau-induced neurodegeneration in Drosophila.

Tau Phosphorylation Sites Work in Concert to Promote Neurotoxicity In Vivo

“…Thus, although in our model cell cycle activation and neuronal death depend on tau phosphorylation (Khurana Dias-Santagata et al, 2007;Fulga et al, 2007;Steinhilb et al, 2007), our data indicate that blocking phosphorylation at restricted sites still induces neurotoxicity that is mediated by TOR signaling and cell cycle activation. These findings strongly suggest that individual SP/TP mutants induce neurodegeneration by the same mechanisms as wild-type tau.…”

“…We showed that blocking phosphorylation of all 14 SP/TP sites in tau by mutating them to alanine markedly inhibited tau-induced neurodegeneration in Drosophila Steinhilb et al, 2007). Conversely, mutation of all SP/TP sites to glutamate generated the pseudophosphorylated tau E14 construct, which is significantly more toxic than tau WT (Khurana et al, 2006;Dias-Santagata et al, 2007;.…”

Identification of Novel Genes That Modify Phenotypes Induced by Alzheimer's β-Amyloid Overexpression in Drosophila

“…Biochemical pathways that are affected in neurodegenerative conditions, such as detoxification, protein clearance, and immunological and stress responses, are conserved between flies and humans (reviewed in Marsh and Thompson 2006). Indeed, analysis of Drosophila models of Huntington's and other expanded polyglutamine-caused conditions (Tsuda et al 2005;Bilen et al 2006), as well as Parkinson's (Scherzer et al 2003;Auluck et al 2005;Kontopoulos et al 2006) and tau-related diseases ( Jackson et al 2002;Mudher et al 2004;Dias-Santagata et al 2007;Fulga et al 2007), has yielded important insight into pathways of neurodegeneration.…”

Adaptive responses to alloxan‐induced mild oxidative stress ameliorate certain tauopathy phenotypes

“…Among the kinases known to phosphorylate tau, JNK and their phosphorylated and thus activated forms decreased with longer treatment periods (Figs S1 and 1A). These results were unexpected, as JNK is also known as stress-activated protein kinase (SAPK) (Zhu et al, 2004;Dias-Santagata et al, 2007). Phospho-JNK levels were increased in cells treated with H 2 O 2 (Fig.…”

“…By contrast, when cells are treated with hydrogen peroxide (H 2 O 2 ), ultraviolet light, menadione, or iron, tau phosphorylation decreases (Zhu et al, 2004). Chronic application of oxidative stress in neuronal cells, Drosophila, and mouse models of tauopathy through genetic manipulations induces neurodegeneration and tau accumulation (Zhu et al, 2004;Dias-Santagata et al, 2007;Kulic et al, 2009). Here, we used a chemical named alloxan to investigate the acute effects of oxidative stress on cellular and mouse models of tauopathy.…”