Comparative analysis of the intracellular responses to disease-related aggregation-prone proteins

Andre Melnik; Valentina Cappelletti; Federico Vaggi; Ilaria Piazza; Marco Tognetti; Carmen Schwarz; Gea Cereghetti; Mennat Allah Ahmed; Martin Soste; Kent Matlack; Natalie de Souza; Attila Csikasz-Nagy; Paola Picotti

doi:10.1016/j.jprot.2020.103862

Comparative analysis of the intracellular responses to disease-related aggregation-prone proteins

Andre Melnik, Valentina Cappelletti, Federico Vaggi, Ilaria Piazza, Marco Tognetti, Carmen Schwarz, Gea Cereghetti, Mennat Allah Ahmed, Martin Soste, Kent Matlack, Natalie de Souza, Attila Csikasz-Nagy, Paola Picotti^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Aggregation-prone proteins (APPs) have been implicated in numerous human diseases but the underlying mechanisms are incompletely understood. Here we comparatively analysed cellular responses to different APPs. Our study is based on a systematic proteomic and phosphoproteomic analysis of a set of yeast proteotoxicity models expressing different human disease-related APPs, which accumulate intracellular APP inclusions and exhibit impaired growth. Clustering and functional enrichment analyses of quantitative proteome-level data reveal that the cellular response to APP expression, including the chaperone response, is specific to the APP, and largely differs from the response to a more generalized proteotoxic insult such as heat shock. We further observe an intriguing association between the subcellular location of inclusions and the location of the cellular response, and provide a rich dataset for future mechanistic studies. Our data suggest that care should be taken when designing research models to study intracellular aggregation, since the cellular response depends markedly on the specific APP and the location of inclusions. Further, therapeutic approaches aimed at boosting protein quality control in protein aggregation diseases should be tailored to the subcellular location affected by inclusion formation. Significance: We have examined the global cellular response, in terms of protein abundance and phosphorylation changes, to the expression of five human neurodegeneration-associated, aggregation-prone proteins (APPs) in a set of isogenic yeast models. Our results show that the cellular response to each APP is unique to that protein, is different from the response to thermal stress, and is associated with processes at the subcellular location of APP inclusion formation. These results further our understanding of how cells, in a model organism, respond to expression of APPs implicated in neurodegenerative diseases like Parkinson's, Alzheimer's, and ALS. They have implications for mechanisms of toxicity as well as of protective responses in the cell. The specificity of the response to each APP means that research models of these diseases should be tailored to the APP in question. The subcellular localization of the response suggest that therapeutic interventions should also be targeted within the cell.

Original language	English
Article number	103862
Journal	Journal Of Proteomics
Volume	225
DOIs	https://doi.org/10.1016/j.jprot.2020.103862
Publication status	Published - 15 Aug 2020

Keywords

Amyloid
Aβ42
FUS
GFP
HTT
Neurodegenerative diseases
Protein aggregation
Quantitative proteomics
TDP43
Yeast
αSyn

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jprot.2020.103862

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Melnik, A., Cappelletti, V., Vaggi, F., Piazza, I., Tognetti, M., Schwarz, C., Cereghetti, G., Ahmed, M. A., Soste, M., Matlack, K., de Souza, N., Csikasz-Nagy, A., & Picotti, P. (2020). Comparative analysis of the intracellular responses to disease-related aggregation-prone proteins. Journal Of Proteomics, 225, Article 103862. https://doi.org/10.1016/j.jprot.2020.103862

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title = "Comparative analysis of the intracellular responses to disease-related aggregation-prone proteins",

abstract = "Aggregation-prone proteins (APPs) have been implicated in numerous human diseases but the underlying mechanisms are incompletely understood. Here we comparatively analysed cellular responses to different APPs. Our study is based on a systematic proteomic and phosphoproteomic analysis of a set of yeast proteotoxicity models expressing different human disease-related APPs, which accumulate intracellular APP inclusions and exhibit impaired growth. Clustering and functional enrichment analyses of quantitative proteome-level data reveal that the cellular response to APP expression, including the chaperone response, is specific to the APP, and largely differs from the response to a more generalized proteotoxic insult such as heat shock. We further observe an intriguing association between the subcellular location of inclusions and the location of the cellular response, and provide a rich dataset for future mechanistic studies. Our data suggest that care should be taken when designing research models to study intracellular aggregation, since the cellular response depends markedly on the specific APP and the location of inclusions. Further, therapeutic approaches aimed at boosting protein quality control in protein aggregation diseases should be tailored to the subcellular location affected by inclusion formation. Significance: We have examined the global cellular response, in terms of protein abundance and phosphorylation changes, to the expression of five human neurodegeneration-associated, aggregation-prone proteins (APPs) in a set of isogenic yeast models. Our results show that the cellular response to each APP is unique to that protein, is different from the response to thermal stress, and is associated with processes at the subcellular location of APP inclusion formation. These results further our understanding of how cells, in a model organism, respond to expression of APPs implicated in neurodegenerative diseases like Parkinson's, Alzheimer's, and ALS. They have implications for mechanisms of toxicity as well as of protective responses in the cell. The specificity of the response to each APP means that research models of these diseases should be tailored to the APP in question. The subcellular localization of the response suggest that therapeutic interventions should also be targeted within the cell.",

keywords = "Amyloid, Aβ42, FUS, GFP, HTT, Neurodegenerative diseases, Protein aggregation, Quantitative proteomics, TDP43, Yeast, αSyn",

author = "Andre Melnik and Valentina Cappelletti and Federico Vaggi and Ilaria Piazza and Marco Tognetti and Carmen Schwarz and Gea Cereghetti and Ahmed, {Mennat Allah} and Martin Soste and Kent Matlack and {de Souza}, Natalie and Attila Csikasz-Nagy and Paola Picotti",

year = "2020",

month = aug,

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doi = "10.1016/j.jprot.2020.103862",

language = "English",

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T1 - Comparative analysis of the intracellular responses to disease-related aggregation-prone proteins

AU - Melnik, Andre

AU - Cappelletti, Valentina

AU - Vaggi, Federico

AU - Piazza, Ilaria

AU - Tognetti, Marco

AU - Schwarz, Carmen

AU - Cereghetti, Gea

AU - Ahmed, Mennat Allah

AU - Soste, Martin

AU - Matlack, Kent

AU - de Souza, Natalie

AU - Csikasz-Nagy, Attila

AU - Picotti, Paola

PY - 2020/8/15

Y1 - 2020/8/15

N2 - Aggregation-prone proteins (APPs) have been implicated in numerous human diseases but the underlying mechanisms are incompletely understood. Here we comparatively analysed cellular responses to different APPs. Our study is based on a systematic proteomic and phosphoproteomic analysis of a set of yeast proteotoxicity models expressing different human disease-related APPs, which accumulate intracellular APP inclusions and exhibit impaired growth. Clustering and functional enrichment analyses of quantitative proteome-level data reveal that the cellular response to APP expression, including the chaperone response, is specific to the APP, and largely differs from the response to a more generalized proteotoxic insult such as heat shock. We further observe an intriguing association between the subcellular location of inclusions and the location of the cellular response, and provide a rich dataset for future mechanistic studies. Our data suggest that care should be taken when designing research models to study intracellular aggregation, since the cellular response depends markedly on the specific APP and the location of inclusions. Further, therapeutic approaches aimed at boosting protein quality control in protein aggregation diseases should be tailored to the subcellular location affected by inclusion formation. Significance: We have examined the global cellular response, in terms of protein abundance and phosphorylation changes, to the expression of five human neurodegeneration-associated, aggregation-prone proteins (APPs) in a set of isogenic yeast models. Our results show that the cellular response to each APP is unique to that protein, is different from the response to thermal stress, and is associated with processes at the subcellular location of APP inclusion formation. These results further our understanding of how cells, in a model organism, respond to expression of APPs implicated in neurodegenerative diseases like Parkinson's, Alzheimer's, and ALS. They have implications for mechanisms of toxicity as well as of protective responses in the cell. The specificity of the response to each APP means that research models of these diseases should be tailored to the APP in question. The subcellular localization of the response suggest that therapeutic interventions should also be targeted within the cell.

AB - Aggregation-prone proteins (APPs) have been implicated in numerous human diseases but the underlying mechanisms are incompletely understood. Here we comparatively analysed cellular responses to different APPs. Our study is based on a systematic proteomic and phosphoproteomic analysis of a set of yeast proteotoxicity models expressing different human disease-related APPs, which accumulate intracellular APP inclusions and exhibit impaired growth. Clustering and functional enrichment analyses of quantitative proteome-level data reveal that the cellular response to APP expression, including the chaperone response, is specific to the APP, and largely differs from the response to a more generalized proteotoxic insult such as heat shock. We further observe an intriguing association between the subcellular location of inclusions and the location of the cellular response, and provide a rich dataset for future mechanistic studies. Our data suggest that care should be taken when designing research models to study intracellular aggregation, since the cellular response depends markedly on the specific APP and the location of inclusions. Further, therapeutic approaches aimed at boosting protein quality control in protein aggregation diseases should be tailored to the subcellular location affected by inclusion formation. Significance: We have examined the global cellular response, in terms of protein abundance and phosphorylation changes, to the expression of five human neurodegeneration-associated, aggregation-prone proteins (APPs) in a set of isogenic yeast models. Our results show that the cellular response to each APP is unique to that protein, is different from the response to thermal stress, and is associated with processes at the subcellular location of APP inclusion formation. These results further our understanding of how cells, in a model organism, respond to expression of APPs implicated in neurodegenerative diseases like Parkinson's, Alzheimer's, and ALS. They have implications for mechanisms of toxicity as well as of protective responses in the cell. The specificity of the response to each APP means that research models of these diseases should be tailored to the APP in question. The subcellular localization of the response suggest that therapeutic interventions should also be targeted within the cell.

KW - Amyloid

KW - Aβ42

KW - FUS

KW - GFP

KW - HTT

KW - Neurodegenerative diseases

KW - Protein aggregation

KW - Quantitative proteomics

KW - TDP43

KW - Yeast

KW - αSyn

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U2 - 10.1016/j.jprot.2020.103862

DO - 10.1016/j.jprot.2020.103862

M3 - Article

C2 - 32535145

AN - SCOPUS:85086575644

SN - 1874-3919

VL - 225

JO - Journal Of Proteomics

JF - Journal Of Proteomics

M1 - 103862

ER -

Comparative analysis of the intracellular responses to disease-related aggregation-prone proteins

Abstract

Keywords

UN SDGs

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