A Drosophila model of the neurodegenerative disease SCA17 reveals a role of RBP-J/Su(H) in modulating the pathological outcome

Abstract

Expanded polyglutamine (polyQ) tract in the human TATA-box-binding protein (hTBP) causes the neurodegenerative disease spinocerebellar ataxia 17 (SCA17). To investigate the pathological effects of polyQ expansion, we established a SCA17 model in Drosophila. Similar to SCA17 patients, transgenic flies expressing a mutant hTBP protein with an expanded polyQ tract (hTBP80Q) exhibit progressive neurodegeneration, late-onset locomotor impairment and shortened lifespan. Microarray analysis reveals that hTBP80Q causes widespread and time-dependent transcriptional dysregulation in Drosophila. In a candidate screen for genetic modifiers, we identified RBP-J/Su(H), a transcription factor that contains Q/N-rich domains and participates in Notch signaling. Knockdown of Su(H) by RNAi further enhances hTBP80Q-induced eye defects, whereas overexpression of Su(H) suppresses such defects. While the Su(H) transcript level is not significantly altered in hTBP80Q-expressing flies, genes that contain Su(H)-binding sites are among those that are dysregulated. We further show that hTBP80Q interacts more efficiently with Su(H) than wild-type hTBP, suggesting that a reduction in the fraction of Su(H) available for its normal cellular functions contributes to hTBP80Q-induced phenotypes. While the Notch signaling pathway has been implicated in several neurological disorders, our study suggests a possibility that the activity of its nuclear component RBP-J/Su(H) may modulate the pathological progression in SCA17 patients.

Drosophila Small Heat Shock Proteins: An Update on Their Features and Functions

“…Alternatively, some toxic polyQ proteins have a higher affi nity for transcription factor than their wild-type counterpart, thereby affecting their normal cellular function(s). This is notably the case for hTBP80Q, which has a high affi nity for suppressor of hairless (Su(H)) (Ren et al 2011 ). While hsp23 , hsp26 and hsp27 are down-regulated in fl ies expressing the toxic hTBP80Q, the involvement of Su(H) in this regulation has not been assessed (Ren et al 2011 ).…”

Prion-Like Characteristics of Polyglutamine-Containing Proteins

“…These genetic models have been used in numerous screens to identify modifiers of polyQ disease toxicity. Factors that have been identified to influence the aggregation state or toxicity associated with pathogenic polyQ protein expression include genes involved in promoting protein folding, suppressing aggregation and degradation (most notably, chaperones) (Krobitsch and Lindquist 2000; Bilen and Bonini 2007; Zhang et al 2010), transcription (Ren et al 2011; Liu et al 2012a; Yamanaka et al 2014), and signal transduction (Giorgini et al 2005; Doumanis et al 2009; Schulte et al 2011). Interestingly, in yeast, expression of a polyQ-expanded Htt exon 1 fragment induces the conversion of yeast prion proteins (e.g., Sup35 and Rnq1) into their self-propagating state (Goehler et al 2010), suggesting that pathogenic polyQ expression affects global protein homeostasis or potentially promotes cross-seeding of other Q-rich proteins, in which nonidentical side chains hydrogen bond within the amyloid core, termed a heterosteric zipper (Eisenberg and Jucker 2012).…”

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

“…Transcription factors such as Su(H), Sp1, TFIIB and NFY are all associated with toxic gain of function, while XBP1 and MyoD are associated with loss of function [187]. Many cellular processes are thought to be involved with these transcription factors, such as the chaperone system, TrkA and notch signalling as well as ER stress response [196][197][198][199][200], illustrating the complexity of SCA diseases and the need for a clear understanding of pathogenic mechanisms.…”