Reference Report

Reference
Citation	Weiss, K.R., Kimura, Y., Lee, W.C., Littleton, J.T. (2012). Huntingtin Aggregation Kinetics and Their Pathological Role in a Drosophila Huntington's Disease Model. Genetics 190(2): 581--600. (Export to RIS)
FlyBase ID	FBrf0217529
Publication Type	Research paper
PubMed ID	22095086
PubMed Abstract	Huntington's disease is a neurodegenerative disorder resulting from expansion of a polyglutamine tract in the Huntingtin protein. Mutant Huntingtin forms intracellular aggregates within neurons, although it is unclear whether aggregates or more soluble forms of the protein represent the pathogenic species. To examine the link between aggregation and neurodegeneration, we generated Drosophila melanogaster transgenic strains expressing fluorescently tagged human huntingtin encoding pathogenic (Q138) or nonpathogenic (Q15) proteins, allowing in vivo imaging of Huntingtin expression and aggregation in live animals. Neuronal expression of pathogenic Huntingtin leads to pharate adult lethality, accompanied by formation of large aggregates within the cytoplasm of neuronal cell bodies and neurites. Live imaging and Fluorescence Recovery After Photobleaching (FRAP) analysis of pathogenic Huntingtin demonstrated that new aggregates can form in neurons within 12 hr, while preexisting aggregates rapidly accumulate new Huntingtin protein within minutes. To examine the role of aggregates in pathology, we conducted haplo-insufficiency suppressor screens for Huntingtin-Q138 aggregation or Huntingtin-Q138-induced lethality, using deficiencies covering ~80% of the Drosophila genome. We identified two classes of interacting suppressors in our screen: those that rescue viability while decreasing Huntingtin expression and aggregation and those that rescue viability without disrupting Huntingtin aggregation. The most robust suppressors reduced both soluble and aggregated Huntingtin levels, suggesting toxicity is likely to be associated with both forms of the mutant protein in Huntington's disease.
DOI	10.1534/genetics.111.133710
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Secondary IDs
Language of Publication	English
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Parent Publication
Publication Type	Journal
Abbreviation	Genetics
Title	Genetics
Publication Year	1916-
ISBN/ISSN	0016-6731
Data from Reference
Aberrations (16)
	Df(2L)BSC109 Df(2L)JS17 Df(2R)59AB Df(2R)59AD Df(2R)AA21 Df(2R)cn9 Df(2R)sple-J1 Df(3L)brm11 Df(3L)BSC33 Df(3L)ED220 Df(3L)st-f13 Df(3L)vin7 Df(3R)H-B79 Df(3R)MAP2 Df(3R)MAP117 Df(3R)Tpl10
Alleles (26)
	Avic\GFP^Scer\UAS.cUa Avic\GFP^{Scer\UAS.T:SV40\nls2} CG5830^c02324 Dfd⁶ Disc\RFP^Scer\UAS.cUa Hsap\HTT^{Q15.Scer\UAS.T:Avic\GFP-EGFP,T:Disc\RFP-mRFP} Hsap\HTT^{Q15.Scer\UAS.T:Avic\GFP-EGFP} Hsap\HTT^{Q15.Scer\UAS.T:Disc\RFP-mRFP} Hsap\HTT^{Q96.Scer\UAS.T:Avic\GFP} Hsap\HTT^{Q138.Scer\UAS.T:Avic\GFP-EGFP,T:Disc\RFP-mRFP} Hsap\HTT^{Q138.Scer\UAS.T:Avic\GFP-EGFP} Hsap\HTT^{Q138.Scer\UAS.T:Disc\RFP-mRFP} lab¹⁴ Mmus\Cd8a^{Scer\UAS.T:Avic\GFP} pb¹ Scer\GAL4^Ccap.PP Scer\GAL4^elav.PLu Scer\GAL4^elav-C155 Scer\GAL4^αTub84B.PL Scer\GAL80^ts.αTub84B Scr⁶ Scr^CP1 Sgs3^T:Avic\GFP T:Avic\GFP^EGFP T:Disc\RFP^mRFP Ubx⁵¹
Constructs (16)
	P{Ccap-GAL4.P} P{GAL4-elav.L} P{Sgs3-GFP} P{tubP-GAL4} P{tubP-GAL80^ts} P{UAS-GFP.nls} P{UAS-GFP.U} P{UAS-HTT.Q15.eGFP.mRFP} P{UAS-HTT.Q15.eGFP} P{UAS-HTT.Q15.mRFP} P{UAS-HTT.Q96.GFP} P{UAS-HTT.Q138.eGFP.mRFP} P{UAS-HTT.Q138.eGFP} P{UAS-HTT.Q138.mRFP} P{UAS-mCD8::GFP.L} P{UAS-RFP.U}
Genes (17)
	Avic\GFP CG5830 Dfd Disc\RFP Hsap\HTT htt lab Mmus\Cd8a mRpS31 pb Scer\GAL4 Scer\GAL80 Scr Sgs3 Syt1 T:Avic\GFP Ubx
Insertions (4)
	P{GawB}elav^C155 P{UAS-HTT.Q138.mRFP}A P{UAS-HTT.Q138.mRFP}B PBac{PB}CG5830^c02324
Natural transposons (1)
	P-element