Lithium rescues toxicity of aggregate-prone proteins in Drosophila by perturbing Wnt pathway

Abstract

We have previously shown that lithium can protect against the polyglutamine toxicity of the Huntington's disease mutation in cell models. Here, we demonstrate for the first time in vivo that lithium can protect against the toxicity caused by aggregate-prone proteins with either polyglutamine or polyalanine expansions in Drosophila. We also show that these protective effects can be partly accounted for by lithium acting through the Wnt/Wg pathway, as a GSK3beta-specific inhibitor and overexpression of dTCF also mediate protective effects. Our data suggest that lithium deserves serious consideration for further studies as a therapeutic for polyglutamine diseases, particularly as it is an established drug that has been used for several decades for chronic treatment of affective disorders.

Full Reversal of Alzheimer's Disease-Like Phenotype in a Mouse Model with Conditional Overexpression of Glycogen Synthase Kinase-3

“…These include diabetes and/or insulin resistance (EldarFinkelman, 2002), muscle hypertrophy (Hardt and Sadoshima, 2002), cancer (Manoukian and Woodgett, 2002), bipolar mood disorder (Klein and Melton, 1996), schizophrenia (Kozlovsky et al, 2002), and other neurodegenerative diseases like Huntington's disease (Carmichael et al, 2002;Berger et al, 2005) and frontotemporal dementia with parkinsonism linked to chromosome 17 (Engel et al, 2005). Therefore, the data reported here on reversibility of alterations secondary to increased GSK-3 activity may have implications in many disease conditions other than AD.…”

Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion

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Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

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