Cryo-EM: Developing ALS Therapies in a Flash Freeze?

Flash freeze frames. The disaggregase Hsp104 pulls out one protein from an aggregate, two amino acids at a time, using a ratchet-like mechanism according to a new cryo-EM study led by Daniel Southworth in collaboration with James Shorter.[Reprinted with permission from Gates et al., 2017, Science/AAAS.]

The inventors of cryo-electron microscopy snapped up the Nobel Prize in Chemistry this month (see October 2017 news). The structural technique, pioneered in the mid-1970s, is emerging as a key approach to draft molecular blueprints of complex intracellular structures including the nuclear pore, which may clog up in ALS (see August 2015 news; for review, see Hoelz et al., 2016).

The strategy recently enabled Daniel Southworth’s team at the University of Michigan to capture molecular snapshots of Hsp104, an enzyme which helps refold aggregated proteins (Gates et al., 2017).The approach is currently being developed by University of Pennsylvania School of Medicine’s James Shorter as a potential therapy for ALS (see September 2017 news). Efforts to optimize this approach using these molecular blueprints, are now underway.

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To learn more about how scientists aim to leverage existing enzymes to bust up inclusions in ALS, check out our recent feature: Breaking up TDP-43 aggregates may be doable.

References

Gates SN, Yokom AL, Lin J, Jackrel ME, Rizo AN, Kendsersky NM, Buell CE, Sweeny EA, Mack KL, Chuang E, Torrente MP, Su M, Shorter J, Southworth DR. Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104. Science. 2017 Jul 21;357(6348):273-279. [PubMed].

Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP.GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):129-33. doi: 10.1038/nature14974. Epub 2015 Aug 26. [PubMed].

Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61. [PubMed].

Further Reading

Earl LA, Falconieri V, Milne JL, Subramaniam S. Cryo-EM: beyond the microscope. Curr Opin Struct Biol. 2017 Jun 21;46:71-78. [PubMed].

Kim HJ, Taylor JP. Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases. Neuron. 2017 Oct 11;96(2):285-297. [PubMed].

Shorter J. Designer protein disaggregases to counter neurodegenerative disease. Curr Opin Genet Dev. 2017 Jun;44:1-8. [PubMed].

aggregates cryo-electron microscopy disaggregase disease-als Hsp104 misfolded proteins Nobel Prize nucleocytoplasmic transport proteostasis tdp-43 topic-preclinical
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