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Comments on Teixeira-Castro, A. et al. (2009) International Worm Meeting "Ataxin-3 protein context and cell-specific factors modulate polyQ-mediated neuronal aggregation in a C. elegans model of Machado-Joseph disease." (0)
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Teixeira-Castro, A., Morimoto, R., & Maciel, P. (2009). Ataxin-3 protein context and cell-specific factors modulate polyQ-mediated neuronal aggregation in a C. elegans model of Machado-Joseph disease presented in International Worm Meeting. Unpublished information; cite only with author permission.
Understanding the basis for neuronal subtype-specific protein aggregation is of central importance for several human neurodegenerative diseases, including Machado-Joseph disease. In this study, we developed a novel Ataxin-3 (ATXN3) pathogenesis model in Caenorhabditis elegans and examined the aggregation profile of human ATXN3 by performing FRAP analysis, in live neuronal cells. We found that full-length ATXN3 aggregates only at high Q-length, not found in human patients, whereas C-terminal ATXN3 causes aggregation and neurotoxicity at a threshold length of 75 glutamines. Analysis of specific neurons in C. elegans, reveals that the ventral nerve cord motor neurons are highly affected. Interestingly, certain sensory neurons of the head contain aggregated foci only when the polyQ-stretch is expressed within ATXN3 protein flanking sequences. Moreover, co-expression of full-length human pathological ATXN3 (below aggregation threshold) with an aggregated species capable of initiating the nucleation events, aggravates the aggregation phenotype and new ATXN3-polyQ co-aggregates are formed also in the sensory neurons of these animals, which are not affected when the two species are expressed alone. These results provide direct evidence that protein context and cell-specific factors are major modifiers of polyQ pathogenesis.