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Protein aggregates caught stalling

Low-complexity protein aggregates are a hallmark of neurodegeneration. High-resolution snapshots of the structure of one such aggregate offer an unprecedented view of how these proteins disrupt crucial cellular functions.
  1. Laura Pontano Vaites

    1. Laura Pontano Vaites is in the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.

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  2. J. Wade Harper

    1. J. Wade Harper is in the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.

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Neurodegenerative diseases are often associated with genetic mutations that cause repetition of short sequences of nucleotides. In the disorders amyotrophic lateral sclerosis (ALS, also known as motor neuron disease) and frontotemporal dementia, such an expansion in a non-protein-coding region of the C9orf72 gene1,2, leads to aberrant translation products that contain repetitive stretches of glycine and alanine amino-acid residues. These ‘poly(GA)’ products form aggregates in neurons, and have been implicated in the disruption of a key cellular process in which complexes called proteasomes degrade proteins3,4. However, the biochemical basis for this disruption, and how it might promote disease, is poorly understood. Writing in Cell, Guo et al.5 precisely map the organizational and structural features of poly(GA) aggregates and associated macromolecular complexes in neurons using a technique called 3D cryo-electron tomography (cryo-ET), to provide direct visualization of how proteasomes are disrupted by poly(GA) proteins.

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Nature 555, 449-451 (2018)

doi: https://doi.org/10.1038/d41586-018-03000-2

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