Yeast Models of Prion-Like Proteins That Cause Amyotrophic Lateral Sclerosis Reveal Pathogenic Mechanisms

Monahan, Zachary; Rhoads, Shannon N; Yee, Debra; Shewmaker, Frank

doi:10.3389/fnmol.2018.00453

Cited by 19 publications

(19 citation statements)

References 89 publications

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“…Thus, its strong absorption of mutational trends for Q and N residues has not been a barrier to such a conservation of prion-like composition. The methodology applied here might also be useful in the analysis of human proteins with N/Q biases, such as those linked to amytrophic lateral sclerosis or huntingtin from Huntington's disease Monahan et al, 2018), or to other non-N/Qbiased prion-forming domains, such as in alpha-synuclein (Watts, 2019). In particular, prion-forming domains from any such proteins that display little or no correlation with general compositional trends in the proteome may be under selection pressure against aggregation, or for a functional role for which compositional sequence parameters are precisely modulated.…”

Section: Discussionmentioning

confidence: 99%

Variable absorption of mutational trends by prion-forming domains during Saccharomycetes evolution

Harrison

2020

PeerJ

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Prions are self-propagating alternative states of protein domains. They are linked to both diseases and functional protein roles in eukaryotes. Prion-forming domains in Saccharomyces cerevisiae are typically domains with high intrinsic protein disorder (i.e., that remain unfolded in the cell during at least some part of their functioning), that are converted to self-replicating amyloid forms. S. cerevisiae is a member of the fungal class Saccharomycetes, during the evolution of which a large population of prion-like domains has appeared. It is still unclear what principles might govern the molecular evolution of prion-forming domains, and intrinsically disordered domains generally. Here, it is discovered that in a set of such prion-forming domains some evolve in the fungal class Saccharomycetes in such a way as to absorb general mutation biases across millions of years, whereas others do not, indicating a spectrum of selection pressures on composition and sequence. Thus, if the bias-absorbing prion formers are conserving a prion-forming capability, then this capability is not interfered with by the absorption of bias changes over the duration of evolutionary epochs. Evidence is discovered for selective constraint against the occurrence of lysine residues (which likely disrupt prion formation) in S. cerevisiae prion-forming domains as they evolve across Saccharomycetes. These results provide a case study of the absorption of mutational trends by compositionally biased domains, and suggest methodology for assessing selection pressures on the composition of intrinsically disordered regions.

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Section: Discussionmentioning

confidence: 99%

Variable absorption of mutational trends by prion-forming domains during Saccharomycetes evolution

Harrison

2020

PeerJ

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“…To assess the implications of these disease-causing variants on chaperone function, we turned to prion propagation models in yeast. Such models have been used extensively to study chaperones and understand the deleterious effects of diseaseassociated mutations on protein folding (40)(41)(42)(43)(44)(45)(46). In yeast, prions are naturally occurring, selfpropagating protein structures that require chaperone networks for their efficient propagation (14).…”

Section: Resultsmentioning

confidence: 99%

Client processing is altered by novel myopathy-causing mutations in the HSP40 J domain

Pullen

Weihl

True

2020

Preprint

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The misfolding and aggregation of proteins is often implicated in the development and progression of degenerative diseases. Heat shock proteins (HSPs), such as the ubiquitously expressed Type II Hsp40 molecular chaperone, DNAJB6, assist in protein folding and disaggregation. Historically, mutations within the DNAJB6 G/F domain have been associated with Limb-Girdle Muscular Dystrophy type 1D, now referred to as LGMDD1, a dominantly inherited degenerative disease. Recently, novel mutations within the J domain of DNAJB6 have been reported in patients with LGMDD1. Since novel myopathy-causing mutations in the Hsp40 J domain have yet to be characterized and both the function of DNAJB6 in skeletal muscle and the clients of this chaperone are unknown, we set out to assess the effect of these mutations on chaperone function using the genetically tractable yeast system. The essential yeast Type II Hsp40, Sis1, is homologous to DNAJB6 and is involved in the propagation of yeast prions. Using phenotypic, biochemical, and functional assays we found that homologous mutations in the Sis1 J domain differentially alter the processing of specific yeast prion strains, as well as a non-prion substrate. These data suggest that the newlyidentified mutations in the J domain of DNAJB6 cause aberrant chaperone function that leads to the pathogenesis in LGMDD1. _______________________________________

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“…Our previous work in yeast models revealed a link between human FUS's cytoplasmic aggregation and toxicity when ectopically expressed (Kryndushkin et al, 2011;Monahan et al, 2017Monahan et al, , 2018. FUS expressed in yeast models displays detergent resistance and dyebinding properties more typical of solid-phase aggregates (Fushimi et al, 2011;Kryndushkin et al, 2011).…”

Section: Fus Toxicity and Aggregation Can Be Altered By Non-pikk Phosphomimetic Substitutionmentioning

confidence: 99%

The prion-like domain of Fused in Sarcoma is phosphorylated by multiple kinases affecting liquid- and solid-phase transitions

Owen

Rhoads

Yee

et al. 2020

MBoC

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Fused in Sarcoma (FUS) is a ubiquitously expressed protein that can phase-separate from nucleoplasm and cytoplasm into distinct liquid-droplet structures. It is predominately nuclear and most of its functions are related to RNA and DNA metabolism. Excessive persistence of FUS within cytoplasmic phase-separated assemblies is implicated in the diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Phosphorylation of FUS's prion-like domain (PrLD), by nuclear PIKK-family kinases following DNA damage, was previously shown to alter FUS's liquid-phase and solid-phase transitions in cell models and in vitro. However, proteomic data suggest FUS's PrLD is phosphorylated at numerous additional sites and it is unknown if other non-PIKK and non-nuclear kinases might be influencing FUS's phase transitions. Here we evaluated disease mutations and stress conditions that increase FUS accumulation into cytoplasmic phase-separated structures. We observed that cytoplasmic liquid-phase structures contain FUS phosphorylated at novel sites, which occured independently of PIKK-family kinases. We engineered phosphomimetic substitutions within FUS's PrLD and observed that mimicking a few phosphorylation sites strongly inhibited FUS solid-phase aggregation, while minimally altering liquid-phase condensation. These effects occured independent of the exact location of the phosphomimetic substitutions, suggesting that modulation of PrLD phosphorylation may offer therapeutic strategies that are specific for solid-phase aggregation observed in disease.

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Yeast Models of Prion-Like Proteins That Cause Amyotrophic Lateral Sclerosis Reveal Pathogenic Mechanisms

Cited by 19 publications

References 89 publications

Variable absorption of mutational trends by prion-forming domains during Saccharomycetes evolution

Variable absorption of mutational trends by prion-forming domains during Saccharomycetes evolution

Client processing is altered by novel myopathy-causing mutations in the HSP40 J domain

The prion-like domain of Fused in Sarcoma is phosphorylated by multiple kinases affecting liquid- and solid-phase transitions

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