A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation

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

doi:10.1073/pnas.1516604113

Cited by 78 publications

(91 citation statements)

References 63 publications

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“…1 of a set of aggregation-prone proteins in the proteome (29). Many of the proteins involved in this metastable subproteome are components of the mitochondrial respiratory chain, an observation consistent with the well-characterized mitochondrial disruption associated with neurodegenerative disorders and specifically with AD (39).…”

Section: Resultssupporting

confidence: 57%

“…To find the AD metastable network, we first carried out a weighted gene correlation network analysis (WGCNA) (33,34) of the set of metastable proteins that we previously identified (29) and of the known components of the overall protein homeostasis system (23) (Materials and Methods). WGCNA is a robust method of performing gene coexpression analysis that has been shown to be particularly effective when large transcriptional datasets are available (33).…”

Section: Resultsmentioning

confidence: 99%

“…By following this approach, we have identified the protein homeostasis components corresponding to the metastable subproteome specifically associated with AD (29). Our results show that the genes corresponding to this metastable subproteome are tightly coexpressed with specific components of the ubiquitin-proteasome and the endosomal-lysosomal pathways, thereby suggesting that metastable proteins with a high risk of aggregation tend to be closely regulated by the trafficking and degradation machineries.…”

mentioning

confidence: 93%

“…As the proteins within the metastable subproteome that are also transcriptionally down-regulated in AD may be particularly significant for the pathology of this disorder (29), it is important to determine the detailed mechanisms of their regulation by the protein homeostasis system. Our goal here, therefore, is to identify the specific components of this system that control a recently identified metastable subproteome associated with AD (29).…”

mentioning

confidence: 99%

“…Our goal here, therefore, is to identify the specific components of this system that control a recently identified metastable subproteome associated with AD (29). To achieve this goal, we adopted the strategy of determining the association between groups of genes by probing their genetic interactions, an approach that is based on the observation that many functionally related genes are coexpressed (30,31).…”

mentioning

confidence: 99%

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

Kundra

Ciryam

Morimoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Alzheimer's disease is the most common cause of dementia. A hallmark of this disease is the presence of aberrant deposits containing by the Aβ peptide (amyloid plaques) and the tau protein (neurofibrillary tangles) in the brains of affected individuals. Increasing evidence suggests that the formation of these deposits is closely associated with the age-related dysregulation of a large set of highly expressed and aggregation-prone proteins, which make up a metastable subproteome. To understand in more detail the origins of such dysregulation, we identify specific components of the protein homeostasis system associated with these metastable proteins by using a gene coexpression analysis. Our results reveal the particular importance of the protein trafficking and clearance mechanisms, including specific branches of the endosomal-lysosomal and ubiquitin-proteasome systems, in maintaining the homeostasis of the metastable subproteome associated with Alzheimer's disease.Alzheimer's disease | protein aggregation | protein homeostasis | supersaturation

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Section: Resultssupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

Kundra

Ciryam

Morimoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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mPOS is a novel mitochondrial trigger of cell death – implications for neurodegeneration

Coyne

Chen

2017

FEBS Letters

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In addition to its central role in energy metabolism, the mitochondrion has many other functions essential for cell survival. When stressed, the multifunctional mitochondria are expected to engender multifaceted cell stress with complex physiological consequences. Potential extra-mitochondrial proteostatic burdens imposed by inefficient protein import have been largely overlooked. Accumulating evidence suggests that a diverse range of pathogenic mitochondrial stressors, which do not directly target the core protein import machinery, can reduce cell fitness by disrupting the proteostatic network in the cytosol. The resulting stress, named mitochondrial precursor overaccumulation stress (mPOS), is characterized by the toxic accumulation of unimported mitochondrial proteins in the cytosol. Here, we review our current understanding of how mitochondrial dysfunction can impact the cytosolic proteome and proteostatic signaling. We also discuss the intriguing possibility that the mPOS model may help untangle the cause-effect relationship between mitochondrial dysfunction and cytosolic protein aggregation, which are probably the two most prominent molecular hallmarks of neurodegenerative disease.

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Defective mitochondrial import as a challenge for cellular protein homeostasis

2023

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Mitochondria are organelles indispensable for the correct functioning of eukaryotic cells. Their significance for cellular homeostasis is manifested by the existence of complex quality control pathways that monitor organellar fitness. Mitochondrial biogenesis relies on the efficient import of mitochondrial precursor proteins, a large majority of which are encoded by nuclear DNA and synthesized in the cytosol. This creates a demand for highly specialized import routes that comprise cytosolic factors and organellar translocases. The passage of newly encoded mitochondrial precursor proteins through the cytosol to the translocase of the outer mitochondrial membrane (TOM) is under tight surveillance. As a result of mitochondrial import defects, mitochondrial precursor proteins accumulate in the cytosol or clog the TOM complex, which in turn stimulates cellular stress responses to minimize the consequences of these challenges. These responses are critical for maintaining protein homeostasis under conditions of mitochondrial stress. The present review summarizes recent advances in the field of mitochondrial protein import quality control and discusses the role of this quality control within the network of cellular mechanisms that maintain the cellular homeostasis of proteins.

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A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation

Cited by 78 publications

References 63 publications

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

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

mPOS is a novel mitochondrial trigger of cell death – implications for neurodegeneration

Defective mitochondrial import as a challenge for cellular protein homeostasis

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