The most common genetic cause of amytrophic lateral sclerosis and frontotemporal dementia is an expanded CCCCGG repeat in C9ORF72, which results in aggregates containing poly-Gly-Ala (poly-GA). Here, cryo-electron tomography of rat primary cultured neurons transfected to express poly-GA tagged with green fluorescent protein revealed that poly-GA aggregates formed twisted, branched ribbon formations. These aggregates were associated with high levels of 26S proteasomes (a key component of the ubiquitin–proteasome system), some of which were stalled in what is normally a transient substrate-processing conformation, suggesting that poly-GA aggregates might alter neuronal proteostasis.
References
Guo, Q. et al. In situ structure of neuronal C9orf72 poly-GA aggregates reveals proteasome recruitment. Cell 172, 696–705 (2018)
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Lewis, S. Untangling the ubiquitin–proteasome system. Nat Rev Neurosci 19, 184 (2018). https://doi.org/10.1038/nrn.2018.26
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DOI: https://doi.org/10.1038/nrn.2018.26