Huntingtin Aggregation Kinetics and Their Pathological Role in a Drosophila Huntington's Disease Model

By Weiss, Kurt R.; Kimura, Yoko et al. | Genetics, February 2012 | Go to article overview

Huntingtin Aggregation Kinetics and Their Pathological Role in a Drosophila Huntington's Disease Model


Weiss, Kurt R., Kimura, Yoko, Lee, Wyan-Ching Mimi, Littleton, J. Troy, Genetics


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.

HUNTINGTON'S disease (HD) is an autosomal dominant neurodegenerative disorder and one of the first characterized members of a family of neurological diseases that result from expansion of a polyglutamine [poly(Q)] tract within the causative protein (Orr and Zoghbi 2007). HD is characterized by neurodegeneration and formation of neuronal intracellular inclusions, primarily in the striatum and cortex, leading to motor impairment, personality disorders, dementia, and ultimately death (Vonsattel et al. 1985; Portera- Cailliau et al. 1995). Currently, HD has no known cure and treatments focus on delaying HD-associated symptoms. The causative mutation in HD is expansion of a CAG tract beyond 35 repeats in exon 1 of the IT15 gene encoding Huntingtin (Htt) (Huntington's Disease Research Collaboration 1993). Similar to other poly(Q)-repeat neurological disorders, abnormal protein conformation(s) secondary to poly(Q) expansion are central to HD pathogenesis (Scherzinger et al. 1997; Persichetti et al. 1999). The expanded poly(Q) Htt protein can exist in multiple states (Hoffner et al. 2005; Nagai et al. 2007), including aberrantly folded monomeric forms, oligomeric microaggregates, fibril states, and larger inclusion body aggregates. It is currently unclear which form (s) of mutant Htt are pathogenic and how the abnormally folded protein causes neuronal toxicity.

Poly(Q) expansion leading to aggregation is a common theme in neurodegenerative disorders. Spinocerebellar ataxias (SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and SCA17), spinal bulbar muscular atrophy (SMBA), and dentatorubral pallidoluysian atrophy (DRPLA) all involve poly(Q) expansion, aggregation, and neurodegeneration (Kimura et al. 2007). Evidence that aggregates are toxic is mostly correlative for these diseases, but several studies support the aggregationtoxicity hypothesis. The threshold of poly(Q) repeat number required for the in vitro aggregation threshold is similar to that required for disease manifestation (Davies et al. 1997; Scherzinger et al. 1999). Longer poly(Q) tracts have faster in vitro aggregation kinetics and result in earlier disease onset (Scherzinger et al. 1999). Similarly, treatments that suppress aggregation, including chaperone overexpression (Carmichael et al. …

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