Apr 16, 2020

Tuning Hsp104 specificity to selectively detoxify alpha-synuclein

BioRxiv : the Preprint Server for Biology
K. L. MackJames Shorter

Abstract

Hsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of alpha-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity, and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress alpha-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, alpha-synuclein-specific Hsp104 variants emerge that mitigate alpha-synuclein toxicity via distinct ATPase-dependent mechanisms, involving alpha-synuclein disaggregation or detoxification of alpha-synuclein conformers without disaggregation. Importantly, both types of alpha-synuclein-specific Hsp104 variant reduce dopaminergic neurodegeneration in a C. elegans model of Parkinson's disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegen...Continue Reading

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Mentioned in this Paper

Biochemical Pathway
DHX9 gene
FOXN3 wt Allele
MRNA Maturation
Deoxyribonuclease I
DNA Repair
DNA Stability
Endonuclease
Complex (molecular entity)
Transcription, Genetic

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