Combating neurodegenerative disease with chemical probes and model systems

Narayan, Priyanka; Ehsani, Sepehr; Lindquist, Susan

doi:10.1038/nchembio.1663

Cited by 44 publications

(32 citation statements)

References 113 publications

(97 reference statements)

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“…[50][51][52][53]146,147 Thus, the power of yeast to elucidate protein-misfolding events and methods to counter them relevant to neurodegenerative disease should not be doubted. 130,137,139 Importantly, for our purposes, the toxicity of TDP-43, FUS, and a-syn in yeast is maintained in Dhsp104 backgrounds, 61 indicating that, unlike polyglutamine toxicity in yeast, [148][149][150] TDP-43, FUS, and a-syn toxicity does not depend on Hsp104 or Hsp104-dependent prions. Moreover, in the Dhsp104 background, overexpression of wild-type (WT) Hsp104 did not rescue TDP-43, FUS, or a-syn toxicity.…”

Section: 2298mentioning

confidence: 99%

“…[122][123][124][125] These yeast models have proven to be an extraordinary resource and have enabled the identification of genetic and small-molecule suppressors of TDP-43, FUS, and a-syn toxicity, which can also exhibit therapeutic efficacy against degeneration in the metazoan nervous system, human cells and neurons, and even patient-derived neurons. 49,114,116,[126][127][128][129][130][131][132][133][134][135][136][137][138] In the case of TDP-43, the yeast model even enabled identification of a common genetic risk factor for ALS: intermediate polyglutamine expansions (27-33 glutamines) in ataxin 2.…”

Section: 2298mentioning

confidence: 99%

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Engineering enhanced protein disaggregases for neurodegenerative disease

Jackrel

Shorter

2015

Prion

103

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ABSTRACT. Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of-function caused by misfolded conformers. Moreover, a disruptive technology of this nature would eliminate self-templating conformers that spread pathology and catalyze formation of toxic, soluble oligomers. Here, we highlight our efforts to engineer Hsp104, a protein disaggregase from yeast, to more effectively disaggregate misfolded proteins connected with PD, ALS, and FTD. Remarkably subtle modifications of Hsp104 primary sequence yielded large gains in protective activity against deleterious a-synuclein, TDP-43, FUS, and TAF15 misfolding. Unusually, in many cases loss of amino acid identity at select positions in Hsp104 rather than specific mutation conferred a robust therapeutic gain-of-function. Nevertheless, the misfolding and toxicity of EWSR1, an RNA-binding protein with a prion-like domain linked to ALS and FTD, could not be buffered by potentiated Hsp104 variants, indicating that further amelioration of disaggregase activity or sharpening of substrate specificity is warranted. We suggest that neuroprotection is achievable for diverse neurodegenerative conditions via surprisingly subtle structural modifications of existing chaperones.

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Section: 2298mentioning

confidence: 99%

Section: 2298mentioning

confidence: 99%

Engineering enhanced protein disaggregases for neurodegenerative disease

Jackrel

Shorter

2015

Prion

103

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“…Impaired autophagy and proteostasis compromised the survival of cancer cells under nutrient starvation. This combination of events can lead to a total collapse of cell functions and proteotoxic cell death (25)(26)(27)47). Mitochondrial dysfunction, impaired proteostasis, and proteotoxic cell death are commonly seen in many neurodegenerative diseases (25-27, 47, 48).…”

Section: Proteotoxic Stat3 Aggregate Formation and In Vivo Antitumormentioning

confidence: 99%

Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells

Genini

Brambilla

Laurini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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In addition to its canonical role in nuclear transcription, signal transducer and activator of transcription 3 (STAT3) is emerging as an important regulator of mitochondrial function. Here, we demonstrate that a novel inhibitor that binds with high affinity to the STAT3 SH2 domain triggers a complex cascade of events initiated by interference with mitochondrial STAT3 (mSTAT3). The mSTAT3-drug interaction leads to mitochondrial dysfunction, accumulation of proteotoxic STAT3 aggregates, and cell death. The cytotoxic effects depend directly on the drug's ability to interfere with mSTAT3 and mitochondrial function, as demonstrated by site-directed mutagenesis and use of STAT3 knockout and mitochondria-depleted cells. Importantly, the lethal consequences of mSTAT3 inhibition are enhanced by glucose starvation and by increased reliance of cancer cells and tumor-initiating cells on mitochondria, resulting in potent activity in cell cultures and tumor xenografts in mice. These findings can be exploited for eliciting synthetic lethality in metabolically stressed cancer cells using highaffinity STAT3 inhibitors. Thus, this study provides insights on the role of mSTAT3 in cancer cells and a conceptual framework for developing more effective cancer therapies.S ignal transducer and activator of transcription 3 (STAT3) is a key element in multiple signaling pathways and is aberrantly activated in many human cancers (1, 2). STAT3 promotes cell proliferation, survival, angiogenesis, and immune-evasion (1-3). Phosphorylation at Tyr705 (pTyr705), catalyzed by Janus kinases (JAK) and other tyrosine kinases, induces STAT3 dimerization through the interaction of the SH2 domain (SH2D), nuclear accumulation, and target gene transcription (1, 3, 4). Emerging evidence indicates that STAT3 also localizes to mitochondria and controls mitochondrial functions (2, 5-7). Mitochondrial localized STAT3 (mSTAT3) is critical for survival of RAStransformed mouse embryo fibroblasts (MEF) under glucosestarvation, reflecting a specific dependency of cancer cells on mitochondria in certain conditions (6). Interestingly, mSTAT3 is prevalently phosphorylated at Ser727 (pSer727), which enhances its mitochondrial functions (5, 6). Furthermore, constitutive pSer727 is found in many human cancers and is apparently sufficient to drive tumorigenesis in various model systems (8-10).STAT3 is an attractive cancer therapeutic target because of its central role in multiple oncogenic processes and great effort has been devoted in recent years to discover STAT3 inhibitors (STAT3i) (11,12). To date, small-molecule STAT3i have shown relevant activity in preclinical models and few of them are currently investigated in clinical trials (11,(13)(14)(15)(16)(17). However, an important gap persists in our knowledge of the biological mechanisms of antitumor activity, the critical cellular processes affected, and the factors determining sensitivity of cancer cells to STAT3i, hindering further clinical development of these highly promising anticancer drugs. Indeed, great atten...

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“…4 These approaches include: inhibition of the enzymes that cleave APP and produce A β , use of compounds that bind to A β and prevent its aggregation, immunization to trigger innate immune reaction against A β , dissolution of plaques for subsequent enzymatic degradation, and prevention of oxidative stress caused by A β aggregates. 5–7 …”

mentioning

confidence: 99%

TANGO-Inspired Design of Anti-Amyloid Cyclic Peptides

Lū

Brickson

Murphy

2016

ACS Chem. Neurosci.

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β-Amyloid peptide (Aβ) self-associates into oligomers and fibrils, in a process that is believed to directly lead to neuronal death in Alzheimer’s disease. Compounds that bind to Aβ, and inhibit fibrillogenesis and neurotoxicity, are of interest as an anti-Alzheimer therapeutic strategy. Peptides are particularly attractive for this purpose, because they have advantages over small molecules in their ability to disrupt protein–protein interactions, yet they are amenable to tuning of their properties through chemical means, unlike antibodies. Self-complementation and peptide library screening are two strategies that have been employed in the search for peptides that bind to Aβ. We have taken a different approach, by designing Aβ-binding peptides using transthyretin (TTR) as a template. Previously, we demonstrated that a cyclic peptide, with sequence derived from the known Aβ-binding site on TTR, suppressed Aβ aggregation into fibrils and protected neurons against Aβ toxicity. Here, we searched for cyclic peptides with improved efficacy, by employing the algorithm TANGO, designed originally to identify amyloidogenic sequences in proteins. By using TANGO as a guide to predict the effect of sequence modifications on conformation and aggregation, we synthesized a significantly improved cyclic peptide. We demonstrate that the peptide, in binding to Aβ, redirects Aβ toward protease-sensitive, nonfibrillar aggregates. Cyclic peptides designed using this strategy have attractive solubility, specificity, and stability characteristics.

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Combating neurodegenerative disease with chemical probes and model systems

Cited by 44 publications

References 113 publications

Engineering enhanced protein disaggregases for neurodegenerative disease

Engineering enhanced protein disaggregases for neurodegenerative disease

Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells

TANGO-Inspired Design of Anti-Amyloid Cyclic Peptides

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