Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases.
Spinocerebellar Ataxia type 1 (SCA1) and Huntington's disease (HD) are two polyglutamine disorders caused by expansion of a CAG repeat within the coding regions of the Ataxin-1 and Huntingtin proteins, respectively. While protein folding and turnover have been implicated in polyglutamine disorders in general, many clinical and pathological differences suggest that there are also disease-specific mechanisms. Taking advantage of a collection of genetic modifiers of expanded Ataxin-1-induced neurotoxicity, we performed a comparative analysis in Drosophila models of the two diseases. We show that while some modifier genes function similarly in SCA1 and HD Drosophila models, others have model-specific effects. Surprisingly, certain modifier genes modify SCA1 and HD models in opposite directions, i.e. they behave as suppressors in one case and enhancers in the other. Furthermore, we find that modulation of toxicity does not correlate with alterations in the formation of neuronal intranuclear inclusions. Our results point to potential common therapeutic targets in novel pathways, and to genes and pathways responsible for differences between Ataxin-1 and Huntingtin-induced neurodegeneration.
Branco
Joana
J
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Al-Ramahi
Ismael
I
Ukani
Lubna
L
Pérez
Alma M
AM
Fernandez-Funez
Pedro
P
Rincón-Limas
Diego
D
Botas
Juan
J
D000818:Animals; D030801:Animals, Genetically Modified; D000067696:Ataxin-1; D000067528:Ataxins; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics; D005799:Genes, Dominant; D017344:Genes, Insect; D020271:Heredodegenerative Disorders, Nervous System / Q000209:etiology* / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000209:etiology / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010455:Peptides / Q000235:genetics*; D010641:Phenotype; D049294:Phospholipid Transfer Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000209:etiology / Q000235:genetics
C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; D029721:Drosophila Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D049294:Phospholipid Transfer Proteins; D011994:Recombinant Proteins; C509515:Vib protein, Drosophila; C097188:polyglutamine; C494917:Akt1 protein, Drosophila; D051057:Proto-Oncogene Proteins c-akt