Designer protein disaggregases to counter neurodegenerative disease

Shorter, James

doi:10.1016/j.gde.2017.01.008

Cited by 72 publications

(94 citation statements)

References 111 publications

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“…However, the observations that SGs co-aggregate with misfolded proteins and that boosting the heat shock response maintains RBP dynamics strongly suggest that upregulation of specific molecular chaperones may represent a valid approach to combat aging and age-related neurodegenerative diseases. Besides the granulostasis machinery, yeast Hsp104 and the mammalian disaggregase machinery composed of HSP110, HSP70 and HSP40 may represent attractive candidates, whose induction may dissolve aggregated RNPs, thus exerting anti-aging protective effects (Shorter, 2011, 2017; Jackrel et al, 2014). Intriguingly, cooperation between the mammalian disaggregase machinery and human small HSPs has been shown to potentiate the dissolution of amyloid aggregates (Duennwald et al, 2012).…”

Section: Emerging Connections Between Stress Granules and Age-relatedmentioning

confidence: 99%

Granulostasis: Protein Quality Control of RNP Granules

Alberti

Matějů

Mediani

et al. 2017

Front. Mol. Neurosci.

128

108

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Ribonucleoprotein (RNP) granules transport, store, or degrade messenger RNAs, thereby indirectly regulating protein synthesis. Normally, RNP granules are highly dynamic compartments. However, because of aging or severe environmental stress, RNP granules, in particular stress granules (SGs), convert into solid, aggregate-like inclusions. There is increasing evidence that such RNA-protein inclusions are associated with several age-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), fronto-temporal dementia (FTD) and Alzheimer’s disease (AD). Thus, understanding what triggers the conversion of RNP granules into aggregates and identifying the cellular players that control RNP granules will be critical to develop treatments for these diseases. In this review article, we discuss recent insight into RNP and SG formation. More specifically, we examine the evidence for liquid-liquid phase separation (LLPS) as an organizing principle of RNP granules and the role of aggregation-prone RNA-binding proteins (RBPs) in this process. We further discuss recent findings that liquid-like SGs can sequester misfolded proteins, which promote an aberrant conversion of liquid SGs into solid aggregates. Importantly, very recent studies show that a specific protein quality control (PQC) process prevents the accumulation of misfolding-prone proteins in SGs and, by doing so, maintains the dynamic state of SGs. This quality control process has been referred to as granulostasis and it relies on the specific action of the HSPB8-BAG3-HSP70 complex. Additional players such as p97/valosin containing protein (VCP) and other molecular chaperones (e.g., HSPB1) participate, directly or indirectly, in granulostasis, and ensure the timely elimination of defective ribosomal products and other misfolded proteins from SGs. Finally, we discuss recent findings that, in the stress recovery phase, SGs are preferentially disassembled with the assistance of chaperones, and we discuss evidence for a back-up system that targets aberrant SGs to the aggresome for autophagy-mediated clearance. Altogether the findings discussed here provide evidence for an intricate network of interactions between RNP granules and various components of the PQC machinery. Molecular chaperones in particular are emerging as key players that control the composition and dynamics of RNP granules, which may be important to protect against age-related diseases.

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Section: Emerging Connections Between Stress Granules and Age-relatedmentioning

confidence: 99%

Granulostasis: Protein Quality Control of RNP Granules

Alberti

Matějů

Mediani

et al. 2017

Front. Mol. Neurosci.

128

108

View full text Add to dashboard Cite

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“…Thus, it is important to develop therapeutics that directly antagonize the underlying toxic protein-misfolding events in neurodegenerative disease. In this way, proteins can be restored to their native conformation and function, which may halt the debilitating trajectory of neurodegeneration Shorter, 2008Shorter, , 2016Shorter, , 2017.…”

Section: Introductionmentioning

confidence: 99%

Tuning Hsp104 specificity to selectively detoxify α-synuclein

Mack

Kim

Jackrel³

et al. 2020

Preprint

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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 α-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 α-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, αsynuclein-specific Hsp104 variants emerge that mitigate α-synuclein toxicity via distinct ATPase-dependent mechanisms, involving α-synuclein disaggregation or detoxification of α-synuclein conformers without disaggregation. Importantly, both types of α-synucleinspecific 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 neurodegenerative disease.

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“…Indeed, UBQLN2 co-localizes with cytoplasmic inclusions in a wide variety of ALS cases (Deng et al, 2011). However, these inclusions could be resolved with therapeutic protein disaggregases (Shorter, 2017). Moving forward, it will be critical to confirm whether UBQLN2 engages ubiquitylated clients inside SGs and removes them from the SG phase for proteasomal degradation in vivo .…”

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confidence: 99%