Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Kundra, Rishika; Ciryam, Prajwal; Morimoto, Richard I.; Dobson, Christopher M.

doi:10.1073/pnas.1618417114

Cited by 79 publications

(64 citation statements)

References 90 publications

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“…In particular, the Bag3 response, being one of the largest differential responses detected, is involved in autophagic pathways, suggests that core chaperone associated degradation pathways associated with autophagy may be central to the management of AM and AT2 cells during aging, as suggested previously for other aging-related aggregation prone states (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). These observations raise the possibility that aging of the lung, a major contributor to the decline of lung function in response to environmental stress over a lifetime (9), is, at least in part, an uncharacterized aggregation prone disease, perhaps in response to supersaturation (83,84) that must be precisely managed by the extensive Bag and DnaJ families through CARE over a lifespan. We also noted that while the Hsp90 core chaperone only exhibited modest changes in abundance (Fig 10), the Hsp90 chaperone/co-chaperone system as a whole underwent large differential changes in both AM and AT2 cells (Fig 4), suggesting that, like observed for Hsp70, it is the CARE network components that dictate the success of the chaperone network to manage the misfolding challenges that arise with aging.…”

Section: Discussionsupporting

confidence: 58%

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

Loguercio

Hutt

Campos

et al. 2019

Preprint

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Aging is associated with an increased risk for the development of many diseases. This is exemplified by the increased incidence of lung injury, muscle dysfunction and cognitive impairment in the elderly following influenza infection. Because the infectious cycle of flu is dependent upon the properties of the host, we examined the proteome of alveolar macrophages (AM) and type 2 cells (AT2) obtained from young (3 months) and old (18 months) naïve mice and mice exposed to influenza A. Our proteomics data show that there is a maladaptive collapse of the proteostasis network (PN) and changes in mitochondrial pathways in the aged naïve AM and AT2 proteomes. The mitochondrial imbalance and proteostatic collapse seen in aged cells places an excessive folding burden on these cells, which is further exacerbated following exposure to influenza A. Specifically, we see an imbalance in Hsp70 co-chaperones involved in protein folding and Hsp90 co-chaperones important for stress signaling pathways that are essential for cellular protection during aging. The acute challenge of influenza A infection of young and aged AM and AT2 cells reveals that age-associated changes in the chaperome affect the ability of these cells to properly manage the infection and post-infection biology, contributing to cytotoxicity. We posit that proteomic profiling of individual cell type specific responses provides a high impact approach to pinpoint fundamental molecular relationships that may contribute to the susceptibility to aging and environmental stress, providing a platform to identify new targets for therapeutic intervention to improve resiliency in the elderly.

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Section: Discussionsupporting

confidence: 58%

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

Loguercio

Hutt

Campos

et al. 2019

Preprint

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“…Of the 5 Panx1-interacting Rabs found in the mouse postsynaptic PPI network (Table 2), Rab11 is specifically known to regulate different aspects of AMPA receptor trafficking within the postsynaptic compartment (reviewed in (Mignogna and D'Adamo, 2018). Another critical membrane trafficking protein, Nsf was present in the cross-analyses for both postsynaptic proteins and Parkinson disease risk genes from the GWAS cross-analysis, and Alzheimer disease (Kundra et al, 2017). In addition to the canonical role it plays working with soluble Nsf attachment protein (SNAP) in the disassembly of protein complexes, Nsf also regulates the trafficking of AMPA receptors (Kiral et al, 2018;Osten et al, 1998;Zhao et al, 2007).…”

Section: Fig 11 Human String Protein-protein Interaction (Ppi) Netwmentioning

confidence: 99%

Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses

Frederiksen

Wicki-Stordeur

Swayne

2019

Preprint

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The Pannexin 1 (Panx1) channel-forming protein is enriched in the central nervous system, and has been associated with several critical neurodevelopmental and plasticity functions; these include dendritic spine formation, neuronal network development, synaptic plasticity, and pathological brain states such as ischemia, epilepsy, and neurodegeneration. Despite major advances in understanding the properties and activation modes of Panx1, the Panx1 interactome remains largely uncharacterized. Considering that Panx1 has been implicated in critical neurodevelopmental and neurodegenerative processes and diseases, we investigated the Panx1 interactome (482 Panx1interacting proteins) identified from mouse N2a cells. These proteins were cross-analyzed with the postsynaptic proteome of the adult mouse brain previously identified by mass spectrometry (LC-MS/MS), and neurodegenerative disease and neurodevelopmental disorder susceptibility genes previously identified by genome-wide association studies (GWAS); and then further investigated using various bioinformatics tools (PAN-THER, GO, KEGG and STRING databases). A total of 104 of the Panx1-interacting proteins were located at the postsynapse, and 99 of these formed a 16-cluster protein-protein interaction (PPI) network (hub proteins: Eef2, Rab6A, Ddx39b, Mapk1, Fh1, Ndufv1 et cetera). The cross-analysis led to the discovery of proteins and candidate genes involved in synaptic function and homeostasis. Of particular note, our analyses also revealed that certain Panx1-interacting proteins are implicated in Parkinson disease, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, schizophrenia, autism spectrum disorder and epilepsy. Altogether, our work revealed important clues to the role of Panx1 in neuronal function in health and disease by expanding our knowledge of the PPI network of Panx1, and unveiling previously unidentified Panx1-interacting proteins and networks involved in biological processes and disease. Panx1 | PPIs | pathway analysis | neurodegenerative diseases | neurodevelopmental disorders | Parkinson disease | Alzheimer disease | chaperones | vesicle-mediated transportFunctional annotation, categorization and overrepresentation analyses of the Panx1 interactome using the PANTHER database. Bioinformatics analysis of all proteins in our Panx1-interacting protein list (using UniProt accession numbers) was carried out using the PANTHER database v14.1 (Mi et al., 2013;Thomas et al., 2003), which is a curated database that includes several bioinformatics tools. The proteins (or their corresponding genes, depending on the nature of the analysis) were annotated to (i) PAN-THER protein classes from the PANTHER protein class ontology, (ii) gene ontology (GO) terms within the biological process, molecular function and cellular component domains from the GO knowledge base and (iii) PANTHER pathways created using the CellDesigner tool, a modelling tool for biochemical networks (Funahashi et al., 2008;Mi et al., 2019a;Mi et al., 2013). Note that PANTHER pa...

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“…Recent studies have proposed that solubility and supersaturation are fundamental factors in understanding protein aggregation in solution. [18][19][20][21][22][23][24][25] Proteins over the solubility limit must form insoluble aggregates such as amyloid fibrils from the thermodynamic point of view. However, apparently soluble proteins prior to the phase transition to insoluble solid states are often detected due to kinetic trapping by the metastability of supersaturation, which is certainly linked to the cause and effect relationship with the nucleation and lag time.…”

Section: Hiv Infections Continue To Be a Major Health Issuementioning

confidence: 99%

“…Recent studies have proposed that solubility and supersaturation are fundamental factors in understanding protein aggregation in solution . Proteins over the solubility limit must form insoluble aggregates such as amyloid fibrils from the thermodynamic point of view.…”

Section: Introductionmentioning

confidence: 99%

Semen‐derived amyloidogenic peptides—Key players of HIV infection

Lee

Ramamoorthy

2018

Protein Science

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Misfolding and amyloid aggregation of intrinsically disordered proteins (IDPs) are implicated in a variety of diseases. Studies have shown that membrane plays important roles on the formation of intermediate structures of IDPs that can initiate (and/or speed-up) amyloid aggregation to form fibers. The process of amyloid aggregation also disrupts membrane to cause cell death in amyloid diseases like Alzheimer's disease and type-2 diabetes. On the other hand, recent studies reported the membrane fusion properties of amyloid fibers. Remarkably, amyloid-fibril formation by short peptide fragments of highly abundant prostatic acidic-phosphatase (PAP) in human semen and are capable of boosting the rate of HIV infection up to 400,000-fold during sexual contact. Unlike the least toxic fully matured fibers of most amyloid proteins, the semen-derived enhancer of virus infection (SEVI) amyloid-fibrils of PAP peptide fragments are highly potent in rendering the maximum rate of HIV infection. This unusual property of amyloid fibers has witnessed increasing number of studies on the biophysical aspects of fiber formation and fiber-membrane interactions. NMR studies have reported a highly disordered partial helical structure in a membrane environment for the intrinsically disordered PAP peptide that promotes the fusion of the viral membrane with that of host cells. The purpose of this review article is to unify and integrate biophysical and immunological research reported in the previous studies on SEVI. Specifically, amyloid aggregation, dramatic HIV infection enhancing properties, membrane fusion properties, high resolution NMR structure, and approaches to eliminate the enhancement of HIV infection of SEVI peptides are discussed.

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Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Cited by 79 publications

References 90 publications

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses

Semen‐derived amyloidogenic peptides—Key players of HIV infection

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