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Quantitative proteomics in a cellular model of human ATXN1(Q82) protein aggregation

ABSTRACT: Spinocerebellar ataxia type-1 is caused by an abnormally expanded polyglutamine (polyQ) tract in ataxin-1 protein. These expansions are responsible for protein misfolding and self-assembly into intranuclear inclusion bodies (IIBs) that are linked to neuronal death. Here, we describe a nuclear protein aggregation model of pathogenic human ataxin-1. Using an inducible Sleeping Beauty transposon system, we overexpressed ATXN1(Q82) in human mesenchymal stem cells that are resistant to the early cytotoxic effects of the mutant protein. We characterized the proteome of cells containing insoluble polyQ IIBs which gradually occupy the nuclei. In response to their formation, our proteomics analysis reveals a perturbed protein interaction network affecting critical cellular processes and indicates major kinases which may affect polyQ protein aggregation.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: David Potesil

LAB HEAD: Zbynek Zdrahal

PROVIDER: PXD038393 | Pride | 2025-02-21

REPOSITORIES: pride

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			Action	DRS
	3034_QEx1_Zdrahal_Petrakis_D01.raw	Raw
	3034_QEx1_Zdrahal_Petrakis_D02.raw	Raw
	3034_QEx1_Zdrahal_Petrakis_D03.raw	Raw
	3034_QEx1_Zdrahal_Petrakis_D101.raw	Raw
	3034_QEx1_Zdrahal_Petrakis_D102.raw	Raw

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Project description:Protein aggregation is a hallmark of many neurodegenerative diseases. In order to cope with misfolding and aggregation, cells have evolved an elaborate network of molecular chaperones, composed of different families. But while chaperoning mechanisms for different families are well established, functional and regulatory diversification within chaperone families is still largely a mystery. Here we decided to explore chaperone functional diversity, through the lens of pathological aggregation. We revealed that different naturally-occurring isoforms of DNAJ chaperones showed differential effects on different types of aggregates. We performed a chaperone screen for modulators of two neurodegeneration-related aggregating proteins, the Huntington’s disease-related HTT-polyQ, and the ALS-related mutant FUS (mutFUS). The screen identified known modulators of HTT-polyQ aggregation, confirming the validity of our approach. Surprisingly, modulators of mutFUS aggregation were completely different than those of HTT-polyQ. Interestingly, different naturally-occurring isoforms of DNAJ chaperones had opposing effects on HTT-polyQ vs. mutFUS aggregation. We identified a complex of the full length (FL) DNAJB14 and DNAJB12 isoforms which substantially alleviated mutFUS aggregation, in an HSP70-dependent manner. Their naturally occurring short isoforms were unable to form the complex, nor to interact with HSP70, and lost their ability to reduce mutFUS aggregation. In contrast, the short isoform of DNAJB12 significantly alleviated HTT-polyQ aggregation, while DNAJB12-FL aggravated HTT-polyQ aggregation. Finally, we demonstrated that full-length DNAJB14 ameliorated mutFUS aggregation compared to DNAJB14-short in primary neurons. Together, our data unraveled distinct molecular properties required for aggregation protection in different neurodegenerative diseases, and revealed a new layer of complexity of the chaperone network elicited by naturally occurring J-protein isoforms, highlighting functional diversity among the DNAJ family.

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Quantitative proteomics in a cellular model of human ATXN1(Q82) protein aggregation

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