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The Stress Response and Stress Proteins
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
Martin E. Feder, Dawn A. Parsell, Susan L. Lindquist
First, experimental studies have now demonstrated that stress proteins are not just correlated with inducible thermotolerance, but are essential for it. Deletion of the HSP104 gene in yeast, for example, results in a marked reduction in inducible thermotolerance, and introduction of the missing HSP104 gene on a plasmid restores inducible thermotolerance1 (Figure 3). Similar results have been obtained for hsp70 by varying cellular hsp70 levels either directly8,9 or through experimental manipulations of the corresponding genes.10–14 Moreover, stress proteins have been shown to confer tolerance to many different forms of stress. Hsp104, for example, improves tolerance to ethanol and arsenite in yeast and is expressed constitutively in spores, the most eurytolerant stage of the yeast life cycle.
Hydrogen deuterium exchange mass spectrometry applied to chaperones and chaperone-assisted protein folding
Published in Expert Review of Proteomics, 2019
Florian Georgescauld, Thomas E. Wales, John R. Engen
HDX MS methodology has also been applied to the AAA+ molecular machinery involved in protein remodeling. One study concerned the mechanism of the AAA+ protein Rubisco activase in the repair of the photosynthetic enzyme Rubisco, a complex of eight large and eight small subunits [58]. Another study used HDX MS to monitor complex formation in Cdc48 [59]. The conformational dynamics of Hsp104, also an AAA+ molecular machine that rescues proteins trapped in amorphous aggregates and stable amyloids, have been studied by HDX MS [60]. Finally, HDX MS was used by the groups of Martin and Hurley to show that the ATPaseVps4 disassembles an ESCRT-III filament by global unfolding and processive translocation [61], while the peroxisomal ATPase Pex1/Pex6 unfolds substrates by processive threading [62]. For all these studies, HDX MS was used to better understand the dynamic aspects of these AAA+ machines during their functional cycle and their interaction(s) with substrates or various partners. The structural information obtained by HDX MS could hardly have been obtained by other structural methods and shows the growing role of this technique in understanding how large protein machines perform their biological functions.
TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target
Published in Expert Opinion on Therapeutic Targets, 2022
Yara Al Ojaimi, Audrey Dangoumau, Hugo Alarcan, Rudolf Hergesheimer, Patrick Vourc’h, Philippe Corcia, Débora Lanznaster, Hélène Blasco
One way to decrease the aggregation of TDP-43 is to direct molecular chaperones such as heat shock proteins (Hsp) against the misfolded protein. Some studies suggest that when Hsp’s fail to properly refold a protein, they recruit co-chaperones that mark these proteins for degradation by the UPS or ALP. Hsp104, a yeast chaperone with a disaggregase activity, was successfully modified to efficiently remove TDP-43 aggregates and restore the nuclear localization of the protein in a yeast model of TDP-43 proteinopathy [69]. The Hsp104 chaperone has no homologue in humans and therefore, strategies aiming at modifying existing human heat shock proteins that have a disaggregase activity such as Hsp70, Hsp110, and Hsp40 can render them more potent in specifically removing TDP-43 aggregates. Several studies have focused on increasing the activity of Hsp’s, to induce the degradation of pathological TDP-43 in cellular or animal models of TDP-43 proteinopathy and reduce TDP-43-mediated toxicity and oxidative stress [70,71]. An interesting study recently described the essential role of Hsp70 in the assembly of aggregation-prone TDP-43 into anisosomes which are spherical droplets with liquid properties [72]. Anisosomes are formed from a self-interacting RNA-unbound TDP-43 shell surrounding an Hsp70 core that maintains the liquidity of these droplets. A drop in cellular ATP levels decreases the activity of Hsp70 chaperones and leads to the conversion of anisosomes into protein aggregates, similar to those observed in ALS [72]. Therefore, maintaining the normal function of Hsp70 chaperones can be used as an early therapeutic intervention that inhibits the progression of TDP-43 droplets into aggregates.
Polyglutamine spinocerebellar ataxias: emerging therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2020
Andreia Neves-Carvalho, Sara Duarte-Silva, Andreia Teixeira-Castro, Patrícia Maciel
While there is an ongoing debate about the contribution of different aggregated species for disease, protein aggregation is a pathological hallmark of polyQ SCAs. Counteracting this process was one of the first proposed therapeutic approaches in the field. This can be achieved through direct interaction of the therapeutic molecule with the mutant protein, suppressing its aggregation by avoiding conformational transitions and/or impeding oligomerization, as proposed for the polyglutamine-binding peptide QBP1, the peptoid HQP09 [61], epigallocatechin-3-gallate [62–64], ectoine [65], methacycline [66], arginine [67], and the chemical chaperones dimethyl sulfoxide (DMSO), glycerol and trimethylamine N-oxide (TMAO) [68]. Alternatively, it can be achieved through potentiation of endogenous protein quality control-promoting pathways. Extensive evidence in various SCA1, SCA3 and SCA17 models supports that overexpression of molecular chaperones has a protective effect, decreasing polyQ aggregation and neurodegeneration, as shown for HSP40, HSP70, HSP104, DNAJC8, DNAJB6, HDJ2/HSDJ, the co-chaperones sacsin and CHIP (Reviewed in [69]). Chaperones may promote folding, disaggregation or degradation of the mutant proteins through the proteasome- or lysosome-mediated pathways (section 3), both of which can be advantageous. Several chaperone-related strategies also proved to reduce aggregation and cell death in cellular polyQ models: HSP90 inhibition (leading to enhanced activity of the master regulator of the heat-shock response, HSF1, and overall chaperone expression) or Protein Kinase C activation [69], small-molecule modulation of HSP70 activity [70], and protection of resident chaperones from degradation by inhibiting their miRNA regulators [71]. Drugs targeting HSP70 and HSP90 have been tested in cellular and animal models of SCA3, with promising results, but not yet for other polyQ SCAs [70,72–74]. Also, due to the poor solubility and variable efficacy of HSP90 inhibitors, new synthetic compounds have been designed, such as BIIB021, PU3 and NVP-AUY922, that demonstrated more potency and/or stability [75,76]. BIIB021, a purine-scaffold HSP90 inhibitor, was shown to reduce accumulation of mutant ATXN1 in a cell model of SCA1, via proteasome and autophagy activity [74]. Compounds designed to target HSF1, such as HSF1A [77,78], have been shown to be efficacious in models of polyQ pathogenesis but also not yet tested in specific SCAs. Several other proteins were shown to directly activate HSF1, such as PKA, PLK1, CK2, IR (through HSF1 phosphorylation), IER5 (through HSF-1 de-phosphorylation), SIRT1 and HDCA6 (via deacetylation), HDAC6 (by disrupting repressive HSP90-HSF1 complexes), and EEF1A1 (helping to recruit HSF1 to the HSP70 promoter to initiate transcription), and therefore may constitute potential therapeutic targets for polyQ SCAs [79].