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Molecular and structural architecture of polyQ aggregates in yeast. | LitMetric

AI Article Synopsis

  • Huntington's disease is linked to the expansion of a polyglutamine tract in the huntingtin protein, but the exact processes causing brain cell death are unclear.
  • Research using yeast models shows that polyQ-expanded huntingtin leads to the creation of disorganized inclusion bodies and sometimes fibrils, differing from observations in mammalian cells.
  • The study reveals that polyQ toxicity affects cell structures like mitochondria and lipid droplets, and alters many cellular proteins, especially those tied to energy metabolism, indicating a complex mechanism of cell damage.

Article Abstract

Huntington's disease is caused by the expansion of a polyglutamine (polyQ) tract in the N-terminal exon of huntingtin (HttEx1), but the cellular mechanisms leading to neurodegeneration remain poorly understood. Here we present in situ structural studies by cryo-electron tomography of an established yeast model system of polyQ toxicity. We find that expression of polyQ-expanded HttEx1 results in the formation of unstructured inclusion bodies and in some cases fibrillar aggregates. This contrasts with recent findings in mammalian cells, where polyQ inclusions were exclusively fibrillar. In yeast, polyQ toxicity correlates with alterations in mitochondrial and lipid droplet morphology, which do not arise from physical interactions with inclusions or fibrils. Quantitative proteomic analysis shows that polyQ aggregates sequester numerous cellular proteins and cause a major change in proteome composition, most significantly in proteins related to energy metabolism. Thus, our data point to a multifaceted toxic gain-of-function of polyQ aggregates, driven by sequestration of endogenous proteins and mitochondrial and lipid droplet dysfunction.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899447PMC
http://dx.doi.org/10.1073/pnas.1717978115DOI Listing

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