Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation

Sacramento, Erika Kelmer; Kirkpatrick, Joanna M; Mazzetto, Mariateresa; Sanzo, Simone Di; Caterino, Cinzia; Sanguanini, Michele; Papaevgeniou, Nikoletta; Lefaki, Maria; Childs, Dorothee; Bagnoli, Sara; Tozzini, Eva Terzibasi; Bartolome, Aleksandar; Romanov, Natalie; Baumgart, Mario; Huber, Wolfgang; Chondrogianni, Niki; Vendruscolo, Michele; Cellerino, Alessandro; Ori, Alessandro

doi:10.1101/577478

Cited by 41 publications

(81 citation statements)

References 72 publications

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“…Promisingly, the investigators found an increase in both total protein aggregation and specific aggregation [Keywords: aneuploidy; protein aggregation; protein homeostasis] of proteins encoded by the duplicated chromosome in almost all 16 strains. The overwhelming majority of proteins that aggregated in all strains were components of ribosomes, an observation consistent with several recent reports linking the aggregation of ribosomal proteins with proteotoxic stresses (Pathak et al 2017;Sacramento et al 2019;Tye et al 2019).…”

supporting

confidence: 90%

“…This study also brings to the fore another phenomenon observed during cancer but also during aging: the loss of protein complex stoichiometry (Janssens et al 2015). Ribosomes (the major components aggregating in the present study) are especially sensitive to this, as shown by a recent study in turquoise killifish, where ribosomal subunits were enriched in aggregates from aged brains (Sacramento et al 2019). Recent advances in global protein complex profiling techniques (e.g., size exclusion chromatography [SEC]-sequential window acquisition of all theoretical mass spectra [SWATH]-MS) (Heusel et al 2019) will undoubtedly prove fruitful for characterizing protein stoichiometry changes under such conditions.…”

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confidence: 51%

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Dosage compensation plans: protein aggregation provides additional insurance against aneuploidy

2019

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Gene dosage alterations caused by aneuploidy are a common feature of most cancers yet pose severe proteotoxic challenges. Therefore, cells have evolved various dosage compensation mechanisms to limit the damage caused by the ensuing protein level imbalances. For instance, for heteromeric protein complexes, excess nonstoichiometric subunits are rapidly recognized and degraded. In this issue of Genes & Development, Brennan et al. (pp. 1031–1047) reveal that sequestration of nonstoichiometric subunits into aggregates is an alternative mechanism for dosage compensation in aneuploid budding yeast and human cell lines. Using a combination of proteomic and genetic techniques, they found that excess proteins undergo either degradation or aggregation but not both. Which route is preferred depends on the half-life of the protein in question. Given the multitude of diseases linked to either aneuploidy or protein aggregation, this study could serve as a springboard for future studies with broad-spanning implications.

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confidence: 90%

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confidence: 51%

Dosage compensation plans: protein aggregation provides additional insurance against aneuploidy

2019

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“…Nevertheless, our results suggest an essential partnership between TDP-43 and HSP70 chaperones in driving and maintaining TDP-43 phase separation. Future efforts are now needed to determine the identities of the TDP-43 acetylases and deacetylases and whether there are age-dependent changes in their activities that may synergize with the known age-dependent decline in proteasome activity (63,64) to mediate stress-induced TDP-43 phase separation in age-related neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

“…The iPSCs were differentiated according to a modified version of Martinez et al (62), based on the established strategy of dual-SMAD inhibition (63,64). iPSC dishes at 60-80% confluency Primary antibodies were diluted in the blocking buffer, and cells were incubated with primary antibody over night at 4ºC.…”

Section: Plasmidsmentioning

confidence: 99%

TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli

Gasior

et al. 2020

Preprint

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One Sentence Summary:Acetylation of TDP-43 drives its phase separation into spherical annuli that form a liquid-insidea-liquid-inside-a-liquid. AbstractThe RNA binding protein TDP-43 naturally phase separates within cell nuclei and forms cytoplasmic aggregates in age-related neurodegenerative diseases. Here we show that acetylation-mediated inhibition of TDP-43 binding to RNA produces co-de-mixing of acetylated and unmodified TDP-43 into symmetrical, intranuclear spherical annuli whose shells and cores have liquid properties. Shells are anisotropic, like liquid crystals. Consistent with our modelling predictions that annulus formation is driven by components with strong self-interactions but weak interaction with TDP-43, the major components of annuli cores are identified to be HSP70 family proteins, whose chaperone activity is required to maintain liquidity of the core. Proteasome inhibition, mimicking reduction in proteasome activity during aging, induces TDP-43-containing annuli in neurons in rodents. Thus, we identify that TDP-43 phase separation is regulated by acetylation, proteolysis, and ATPase-dependent chaperone activity of HSP70.A seminal discovery in the last decade has been recognition that large biological molecules, especially RNA binding proteins, can undergo liquid-liquid phase separation (LLPS), resembling oil droplets in vinegar. Under certain physical conditions, proteins, nucleic acids, or a mixture of both in a complex solution can form two phases, a condensed de-mixed phase and more dilute aqueous phase (1). Inside the cell, proteins and/or nucleic acids de-mix into a condensed phase to form membraneless organelles which have been proposed to promote biological functions (2).One membraneless organelle is the nucleolus, first described in the early 1800's and now recognized to be composed of proteins that undergo LLPS (3-5). Discovery that P-granules are de-mixed compartments with liquid behaviour brought widespread recognition to LLPS and its ability to mediate subcellular compartmentalization in a biological context (6). Phase separation has been also proposed for heterochromatin and RNA bodies (1, 6, 7). LLPS potentially underlies the operational principle governing formation of important organelles and structures, such as centrosomes, nuclear pore complexes, and super enhancers (8-10).Few mechanisms to modulate intracellular LLPS have been identified. Disease-causing mutations of proteins such as FUS (11) and HNRNPA2B1 (12) alter their LLPS behaviors in vitro, but the physiological or pathological relevance of their intracellular LLPS has not been fully elucidated. Random, multivalent interactions among intrinsically disordered, low complexity domains (LCDs) of proteins are a major driving force for LLPS in vitro. Oligomerization of other domains is thought to be required for LLPS in vivo (13). The inherent randomness of multivalent interactions (14) favors a model of disordered alignment -a conventional liquid phase in which molecules randomly move. The evidence is compelling that multi...

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“…Intriguingly, recent studies have also indicated that ribosomes are especially susceptible to the protein aggregates that are formed either due to abnormal protein stoichiometry during aneuploidy or due to protein aggregation in aged brains 40,41 . Our recent and earlier 13 studies suggest that the ribosome when placed in the vicinity of protein aggregate formation have a tendency to co-aggregate, thereby providing a plausible explanation to the predominance of ribosomal proteins in the aggregates observed in these studies 40,41 . The inhibition of tau-ribosome electrostatic interactions in the presence of added polyanions, like heparin and tRNA, indeed could inhibit K18 induced tau aggregation.…”

Section: Scientific Reports |mentioning

confidence: 99%

Tau protein- induced sequestration of the eukaryotic ribosome: Implications in neurodegenerative disease

Banerjee

Ferdosh

Ghosh

et al. 2020

Sci Rep

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the human tau is a microtubule-associated intrinsically unstructured protein that forms intraneuronal cytotoxic deposits in neurodegenerative diseases, like tauopathies. Recent studies indicate that in Alzheimer's disease, ribosomal dysfunction might be a crucial event in the disease pathology. our earlier studies had demonstrated that amorphous protein aggregation in the presence of ribosome can lead to sequestration of the ribosomal components. The present study aims at determining the effect of incubation of the full-length tau protein (Ht40) and its microtubule binding 4-repeat domain (K18) on the eukaryotic ribosome. our in vitro studies show that incubation of Ht40 and the K18 tau variants with isolated non-translating yeast ribosome can induce a loss of ribosome physical integrity resulting in formation of tau-rRnA-ribosomal protein aggregates. incubation with the tau protein variants also led to a disappearance of the peak indicating the ribosome profile of the HeLa cell lysate and suppression of translation in the human in vitro translation system. the incubation of tau protein with the ribosomal RNA leads to the formation of tau-rRNA aggregates. The effect of K18 on the yeast ribosome can be mitigated in the presence of cellular polyanions like heparin and tRnA, thereby indicating the electrostatic nature of the aggregation process.

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Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation

Cited by 41 publications

References 72 publications

Dosage compensation plans: protein aggregation provides additional insurance against aneuploidy

Dosage compensation plans: protein aggregation provides additional insurance against aneuploidy

TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli

Tau protein- induced sequestration of the eukaryotic ribosome: Implications in neurodegenerative disease

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