SRCP1 Conveys Resistance to Polyglutamine Aggregation

Santarriaga, Stephanie; Haver, Holly N.; Kanack, Adam; Fikejs, Alicia; Sison, Samantha L.; Egner, John M.; Bostrom, Jonathan R.; Seminary, Emily R; Hill, Rolla B.; Link, Brian A.; Ebert, Allison D.; Scaglione, K. Matthew

doi:10.1016/j.molcel.2018.07.008

Cited by 13 publications

(36 citation statements)

References 55 publications

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“…In this context, it is worth noting that the proteome of D. discoideum was shown recently to harbor highly abundant low complexity stretches with extended poly glutamine (polyQ) and poly asparagine (polyN) stretches, which in wild type cells do not lead to protein aggregation ( 59 , 65 ), unlike observed for yeast and other organisms ( 67 , 68 ). In the amoeba, this resilience against protein aggregation can be accounted for by the high activity of chaperones that apparently counteracts amyloid formation ( 59 , 65 , 69 ). Therefore, we have addressed whether protein misfolding and/or distorted protein expression can be observed in the mutant strains of the Elongator-dependent modification pathway.…”

Section: Discussionmentioning

confidence: 99%

Eukaryotic life without tQCUG: the role of Elongator-dependent tRNA modifications in Dictyostelium discoideum

Schäck

Jablonski

Gräf

et al. 2020

Nucleic Acids Research

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Abstract In the Elongator-dependent modification pathway, chemical modifications are introduced at the wobble uridines at position 34 in transfer RNAs (tRNAs), which serve to optimize codon translation rates. Here, we show that this three-step modification pathway exists in Dictyostelium discoideum, model of the evolutionary superfamily Amoebozoa. Not only are previously established modifications observable by mass spectrometry in strains with the most conserved genes of each step deleted, but also additional modifications are detected, indicating a certain plasticity of the pathway in the amoeba. Unlike described for yeast, D. discoideum allows for an unconditional deletion of the single tQCUG gene, as long as the Elongator-dependent modification pathway is intact. In gene deletion strains of the modification pathway, protein amounts are significantly reduced as shown by flow cytometry and Western blotting, using strains expressing different glutamine leader constructs fused to GFP. Most dramatic are these effects, when the tQCUG gene is deleted, or Elp3, the catalytic component of the Elongator complex is missing. In addition, Elp3 is the most strongly conserved protein of the modification pathway, as our phylogenetic analysis reveals. The implications of this observation are discussed with respect to the evolutionary age of the components acting in the Elongator-dependent modification pathway.

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Section: Discussionmentioning

confidence: 99%

Eukaryotic life without tQCUG: the role of Elongator-dependent tRNA modifications in Dictyostelium discoideum

Schäck

Jablonski

Gräf

et al. 2020

Nucleic Acids Research

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“…It was already known that Dictyostelium cells are quite resistant to protein misfolding and aggregation, a hallmark of several neurodegenerative diseases (Santarriaga et al, 2015;. Recent work has allowed to identifying the serine-rich chaperone protein 1 (SRCP1) as a molecular chaperone necessary and sufficient in Dictyostelium to suppress poly-Q expanded protein aggregation, leading to their degradation in proteasomes (Santarriaga et al, 2018).…”

Section: Dictyostelium As a Model For Biomedical Research: Recent Conmentioning

confidence: 99%

“…There are, clearly, some limitations that make studies with lower organisms still unavoidable (Rine, 2014). Human disease phenotypes in many cases do not provide clues about the underlying molecular defect, thus unbiased genetic experiments in experimentally tractable organisms are required to establish Human disease or biomedical research Most recent reviews or relevant papers Microbial infections and host-pathogen interactions Cardenal-Muñoz et al, 2018;Swart et al, 2018;Steiner et al 2018;Koliwer-Brandl et al 2019;Brenz et al 2017 Mitochondrial diseases Chen et al 2017Chen et al , 2018Annesley et al 2014 Neuronal lipoid lipofuscinosis McLaren et al 2019;Smith et al, 2019 Poly-Q diseases Santarriaga et al 2018; Shwachman-Bodian-Diamond syndrome Weis et al, 2015 Pharmacogenetic research Wauters et al, 2019;Cocorocchio et al 2018;Kubohara and Kikuchi, 2018;Kubohara et al 2019;Arioka et al 2017;Dubois et al 2016…”

Section: Is There a Future For Dictyostelium As A Model Organism?mentioning

confidence: 99%

The past, present and future of Dictyostelium as a model system

Bozzaro¹

2019

Int. J. Dev. Biol.

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The social amoeba Dictyostelium discoideum has been a preferred model organism during the last 50 years, particularly for the study of cell motility and chemotaxis, phagocytosis and macropinocytosis, intercellular adhesion, pattern formation, caspase-independent cell death and more recently autophagy and social evolution. Being a soil amoeba and professional phagocyte, thus exposed to a variety of potential pathogens, D. discoideum has also proven to be a powerful genetic and cellular model for investigating host-pathogen interactions and microbial infections. The finding that the Dictyostelium genome harbours several homologs of human genes responsible for a variety of diseases has stimulated their analysis, providing new insights into the mechanism of action of the encoded proteins and in some cases into the defect underlying the disease. Recent technological developments have covered the genetic gap between mammals and non-mammalian model organisms, challenging the modelling role of the latter. Is there a future for Dictyostelium discoideum as a model organism? Peculiarities and advantages of Dictyostelium discoideum as model organismAmong the non-mammalian model organisms, Dictyostelium discoideum (in the following Dictyostelium) is unique, due to cell division and development being totally uncoupled, and because of the transition from a unicellular to a multicellular stage during the life cycle. Growing cells proliferate by binary fission but do not differentiate, whereas starving cells undergo multicellular development and differentiation without dividing and without any need for external nutrients. Thus growth and development can be studied separately, and several non-lethal mutants can be isolated

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“…In previous studies we used a forward genetic screen to identify a single Dictyostelium discoideum specific gene that is necessary and sufficient to reduce polyglutamine aggregation in cell culture, zebrafish, and iPSC-derived neurons [16]. This gene encodes an ~9kD protein, termed serine-rich chaperone protein 1 (SRCP1), that selectively recognizes and targets aggregation-prone, polyQexpanded protein.…”

Section: Introductionmentioning

confidence: 99%

The novel chaperone protein SRCP1 reduces insoluble SOD1 protein in vivo without extending ALS mouse lifespan

Luecke

Lin

Santarriaga

et al. 2020

Preprint

Self Cite

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Protein misfolding and aggregation are shared features of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and protein quality control disruption contributes to neuronal toxicity. Therefore, reducing protein aggregation could hold therapeutic potential. We previously identified a novel chaperone protein, serine-rich chaperone protein 1 (SRCP1), that effectively prevents protein aggregation in cell culture and zebrafish models of Huntington’s disease. Here we tested whether this benefit extends to aggregated proteins found in ALS. We used viral-mediated expression of SRCP1 in in vitro and in vivo models of ALS. We found that SRCP1 reduced insoluble SOD1 protein levels in HEK293T cells overexpressing either the A4V or G93R mutant SOD1. However, the reduction of insoluble protein was not observed in either mutant C9orf72 or SOD1 ALS iPSC-derived motor neurons infected with a lentivirus expressing SRCP1. SOD1 G93A ALS mice injected with AAV-SRCP1 showed a small but significant reduction in insoluble and soluble SOD1 in both the brain and spinal cord, but SRCP1 expression did not improve mouse survival. These data indicate that SRCP1 likely reduces insoluble protein burden in a protein and/or context-dependent manner indicating a need for additional insight into SRCP1 function and therapeutic potential.

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SRCP1 Conveys Resistance to Polyglutamine Aggregation

Cited by 13 publications

References 55 publications

Eukaryotic life without tQCUG: the role of Elongator-dependent tRNA modifications in Dictyostelium discoideum

Eukaryotic life without tQCUG: the role of Elongator-dependent tRNA modifications in Dictyostelium discoideum

The past, present and future of Dictyostelium as a model system

The novel chaperone protein SRCP1 reduces insoluble SOD1 protein in vivo without extending ALS mouse lifespan

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