Structure of Calcarisporiella thermophila Hsp104 Disaggregase that Antagonizes Diverse Proteotoxic Misfolding Events

Michalska, K.; Zhang, Kaiming; March, Zachary M.; Hatzos-Skintges, C.; Pintilie, Grigore; Bigelow, L.; Castellano, Laura M.; Miles, Leann; Jackrel, Meredith E.; Chuang, Edward; Jedrzejczak, R.; Shorter, James; Chiu, Wah; Joachimiak, A.

doi:10.1016/j.str.2018.11.001

Cited by 33 publications

(48 citation statements)

References 70 publications

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“…Indeed, we reported that an Hsp104 homolog from the thermophilic fungus Calcarisporiella thermophila antagonizes toxicity of TDP-43, αSyn, and polyglutamine in yeast without apparent toxic off-target effects [27]. These findings support our hypothesis that natural Hsp104 homologs may have therapeutically beneficial properties.…”

Section: Introductionsupporting

confidence: 82%

“…Next, we tested the activity of several Hsp104 homologs (ScHsp104, CtHsp104, TtHsp104, AtHsp104, and MtHsp104) against an ordered amyloid substrate, semen-derived enhancer of viral infection (SEVI) [69]. As previously reported [27,53], all Hsp104 homologs tested rapidly remodeled SEVI fibrils ( Figure S8A). Electron microscopy revealed that Hsp104 homologs remodeled SEVI fibrils into small, amorphous structures ( Figure S8B).…”

Section: Differential Suppression Of Proteotoxicity By Hsp104 Homologmentioning

confidence: 53%

“…In yeast, galactose-inducible expression of several proteins associated with neurodegenerative diseases, including aSyn [39], TDP-43 [40], and FUS [13] is toxic. However, coexpression of potentiated Hsp104 variants or the natural homolog Calcarisporiella thermophila Hsp104 (CtHsp104), but not ScHsp104, reduces this toxicity [27,30,33,37]. For a deeper exploration of natural Hsp104 Table S1 for homolog sequences, Figures S1 for an alignment of all homologs).…”

Section: Diverse Hsp104 Homologs Selectively Suppress Tdp-43 Toxicitymentioning

confidence: 99%

“…Wild-type Hsp104 from S. cerevisiae does not protect C. elegans DA neurons in this context [30]. Surprisingly, CtHsp104 also does not affect C. elegans DA neuron survival (Figure 4B-C), despite robust suppression of αSyn-mediated toxicity and inclusion formation in yeast (Figure 2) [27]. This lack of neuroprotection by CtHsp104 may be due to the fact that it is promiscuous.…”

Section: αSyn-selective Hsp104 Homologs Prevent Dopaminergic Neurodegmentioning

confidence: 99%

“…Hsp104 assembles into asymmetric ring-shaped hexamers that undergo conformational changes upon ATP binding and hydrolysis, which drive substrate translocation across the central channel to power protein disaggregation [17,[22][23][24][25][26][27]. Each protomer is comprised of an N-terminal domain (NTD), nucleotidebinding domain 1 (NBD1), a middle domain (MD), NBD2, and a short C-terminal domain [22,23].…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic genetic variation revealed in diverse Hsp104 homologs

March

Sweeney

Kim

et al. 2020

Preprint

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The AAA+ protein disaggregase, Hsp104, increases fitness under stress by reversing stress-induced protein aggregation. We have engineered potentiated Hsp104 variants to antagonize proteotoxic misfolding linked to human neurodegenerative diseases. However, these Hsp104 variants can exhibit offtarget toxicity, which may limit their therapeutic utility. Hsp104 is conserved among all nonmetazoan eukaryotes, which raises the possibility that natural variants might exist with enhanced, selective activity against neurodegenerative disease substrates. To assess this possibility, we screened a cross-kingdom collection of Hsp104 homologs in several yeast proteotoxicity models. We uncovered therapeutic genetic variation among several Hsp104 homologs that specifically antagonize TDP-43 or a-synuclein condensate formation and toxicity in yeast, human cells, and C. elegans. Surprisingly, this variation manifested as increased passive chaperone activity, distinct from disaggregase activity, which neutralizes proteotoxicity of specific substrates. Thus, by exploring natural tuning of passive chaperone activity we elucidated enhanced, substrate-specific agents to counter proteotoxicity underlying neurodegenerative disease.

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Section: Introductionsupporting

confidence: 82%

Section: Differential Suppression Of Proteotoxicity By Hsp104 Homologmentioning

confidence: 53%

Section: Diverse Hsp104 Homologs Selectively Suppress Tdp-43 Toxicitymentioning

confidence: 99%

Section: αSyn-selective Hsp104 Homologs Prevent Dopaminergic Neurodegmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Therapeutic genetic variation revealed in diverse Hsp104 homologs

March

Sweeney

Kim

et al. 2020

Preprint

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Drivers of Hsp104 potentiation revealed by scanning mutagenesis of the middle domain

et al. 2021

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AAA+ Protein-Based Technologies to Counter Neurodegenerative Disease

March

Mack

Shorter

2019

Biophysical Journal

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Protein misfolding and overloaded proteostasis networks underlie a range of neurodegenerative diseases. No cures exist for these diseases, but developing effective therapeutic agents targeting the toxic, misfolded protein species in disease is one promising strategy. AAAþ (ATPases associated with diverse cellular activities) protein translocases, which naturally unfold and translocate substrate proteins, could be potent therapeutic agents to disassemble toxic protein conformers in neurodegenerative disease. Here, we discuss repurposing AAAþ protein translocases Hsp104 and proteasome-activating nucleotidase (PAN) to alleviate the toxicity from protein misfolding in neurodegenerative disease. Hsp104 effectively protects various animal models from neurodegeneration underpinned by protein misfolding, and enhanced Hsp104 variants strongly counter neurodegenerative disease-associated protein misfolding toxicity in yeast, Caenorhabditis elegans, and mammalian cells. Similarly, a recently engineered PAN variant (PAN et ) mitigates photoreceptor degeneration instigated by protein misfolding in a mouse model of retinopathy. Further study and engineering of AAAþ translocases like Hsp104 and PAN will reveal promising agents to combat protein misfolding toxicity in neurodegenerative disease.

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Structure of Calcarisporiella thermophila Hsp104 Disaggregase that Antagonizes Diverse Proteotoxic Misfolding Events

Cited by 33 publications

References 70 publications

Therapeutic genetic variation revealed in diverse Hsp104 homologs

Therapeutic genetic variation revealed in diverse Hsp104 homologs

Drivers of Hsp104 potentiation revealed by scanning mutagenesis of the middle domain

AAA+ Protein-Based Technologies to Counter Neurodegenerative Disease

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