Dataset Information

Stress granules protect ER-exit sites from TDP43 aggregation

ABSTRACT: Aggregation of proteins under cellular stress plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and physiological consequences is poorly understood. We employed a general reporter to identify proteins forming aggregates under proteotoxic stress in human cells. Over 300 proteins were identified, forming different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule (SG) and a previously unknown solid inclusion containing components of the ER exit sites (ERES), such as SEC16A. TDP43 accumulation at ERES is antagonized by SG assembly, but enhanced by certain ALS-associated mutations. TDP43-ERES aggregation biases toward nascent TDP43 and, unlike SG, does not contain RNA. Such aggregation causes defects in ER-to-Golgi protein transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patient neurons.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Rong Li

PROVIDER: PXD041480 | JPOST Repository | Fri Apr 12 00:00:00 BST 2024

REPOSITORIES: jPOST

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			Action	DRS
	20190611_Human_UniProt.fasta	Fasta
	20210119_JW_HY_Agg_.msf	Msf
	20210119_JW_HY_Agg_.pdResult	Other
	20210119_JW_HY_Agg_14pc.raw	Raw
	20210119_JW_HY_Agg_24pc.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.

Project description:Auer2010 - Correlation between lag time and aggregation rate in protein aggregation This model is described in the article: Insight into the correlation between lag time and aggregation rate in the kinetics of protein aggregation. Auer S, Kashchiev D. Proteins 2010 Aug; 78(11): 2412-2416 Abstract: Under favorable conditions, many proteins can assemble into macroscopically large aggregates such as the amyloid fibrils that are associated with Alzheimer's, Parkinson's, and other neurological and systemic diseases. The overall process of protein aggregation is characterized by initial lag time during which no detectable aggregation occurs in the solution and by maximal aggregation rate at which the dissolved protein converts into aggregates. In this study, the correlation between the lag time and the maximal rate of protein aggregation is analyzed. It is found that the product of these two quantities depends on a single numerical parameter, the kinetic index of the curve quantifying the time evolution of the fraction of protein aggregated. As this index depends relatively little on the conditions and/or system studied, our finding provides insight into why for many experiments the values of the product of the lag time and the maximal aggregation rate are often equal or quite close to each other. It is shown how the kinetic index is related to a basic kinetic parameter of a recently proposed theory of protein aggregation. This model is hosted on BioModels Database and identified by: BIOMD0000000555. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.