ArticleThe Journal of biological chemistry2014
Misfolded polyglutamine, polyalanine, and superoxide dismutase 1 aggregate via distinct pathways in the cell.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 42 citations in OpenAlex.
- High-content analysis of proteostasis capacity in cellular models of amyotrophic lateral sclerosis (ALS).Scientific reports · 2024Article
- Nuclear and cytoplasmic spatial protein quality control is coordinated by nuclear-vacuolar junctions and perinuclear ESCRT.Nature cell biology · 2023Article
- The sequence context in poly-alanine regions: structure, function and conservation.Bioinformatics (Oxford, England) · 2022Article
- Sequence grammar underlying the unfolding and phase separation of globular proteins.Molecular cell · 2022Article
- Differentiation Drives Widespread Rewiring of the Neural Stem Cell Chaperone Network.Molecular cell · 2020Article
- Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises.Frontiers in cellular neuroscience · 2020Article
- Article
- Addition of exogenous SOD1 aggregates causes TDP-43 mislocalisation and aggregation.Cell stress & chaperones · 2017Article
- The heat shock response in neurons and astroglia and its role in neurodegenerative diseases.Molecular neurodegeneration · 2017Review
- A thiol probe for measuring unfolded protein load and proteostasis in cells.Nature communications · 2017Article
- Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms.Molecular neurobiology · 2016Review
- Polyalanine expansions drive a shift into α-helical clusters without amyloid-fibril formation.Nature structural & molecular biology · 2015Article
- The ER Stress Surveillance (ERSU) pathway regulates daughter cell ER protein aggregate inheritance.eLife · 2015Article
- Distinct partitioning of ALS associated TDP-43, FUS and SOD1 mutants into cellular inclusions.Scientific reports · 2015Article
- Protein Folding and Mechanisms of Proteostasis.International journal of molecular sciences · 2015Review
- TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2015Review
- Dynamic droplets: the role of cytoplasmic inclusions in stress, function, and disease.Cellular and molecular life sciences : CMLS · 2015Review
- SerpinB2 (PAI-2) Modulates Proteostasis via Binding Misfolded Proteins and Promotion of Cytoprotective Inclusion Formation.PloS one · 2015Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein aggregation into intracellular inclusions is a key feature of many neurodegenerative disorders. A common theme has emerged that inappropriate self-aggregation of misfolded or mutant polypeptide sequences is detrimental to cell health. Yet protein quality control mechanisms may also deliberately cluster them together into distinct inclusion subtypes, including the insoluble protein deposit (IPOD) and the juxtanuclear quality control (JUNQ). Here we investigated how the intrinsic oligomeric state of three model systems of disease-relevant mutant protein and peptide sequences relates to the IPOD and JUNQ patterns of aggregation using sedimentation velocity analysis. Two of the models (polyalanine (37A) and superoxide dismutase 1 (SOD1) mutants A4V and G85R) accumulated into the same JUNQ-like inclusion whereas the other, polyglutamine (72Q), formed spatially distinct IPOD-like inclusions. Using flow cytometry pulse shape analysis (PulSA) to separate cells with inclusions from those without revealed the SOD1 mutants and 37A to have abruptly altered oligomeric states with respect to the nonaggregating forms, regardless of whether cells had inclusions or not, whereas 72Q was almost exclusively monomeric until inclusions formed. We propose that mutations leading to JUNQ inclusions induce a constitutively "misfolded" state exposing hydrophobic side chains that attract and ultimately overextend protein quality capacity, which leads to aggregation into JUNQ inclusions. Poly(Q) is not misfolded in this same sense due to universal polar side chains, but is highly prone to forming amyloid fibrils that we propose invoke a different engagement mechanism with quality control.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.