Disinhibition of NF-κB toxicity leads to dendrite defects in neurodegenerative diseases

Abstract

Dendrite pathology have been observed in several neurodegenerative diseases (NDs). Although many studies have identified a few pathogenic mediators of dendrite defects that act through loss-of-function in NDs, the underlying pathogenic mechanisms of the dendrite defects remain still largely unknown. Here, I identify Relish/NF-κB as a novel gain-of-toxicity-based mediator of dendrite defects in polyglutamine (polyQ) diseases and amyotrophic lateral sclerosis (ALS). In a Drosophila model for spinocerebellar ataxia type 3/Machado Joseph Disease (SCA3/MJD), a one of the polyQ disease, dendrite defects caused by toxic MJD proteins require Dredd/Caspase-8-mediated endoproteolytic cleavage of Relish to generate its N-terminal fragment, Rel68, and subsequent nuclear localization of Rel68 mediated by Charon. Furthermore, overexpression of Rel68 alone results in neuronal toxicity causing dendrite and behavioral defects in cell-autonomous manner, and I identify two novel transcriptional targets, Tup and Pros, that mediate Rel68-induced neuronal toxicity. Finally, I show that Rel68-induced neuronal toxicity contributes to dendrite and behavioral defects in a Drosophila model for ALS. Collectively, my findings suggest disinhibition of latent toxicity of Relish/NF-κB as a novel pathogenic mechanism underlying dendrite pathology in NDs.