UBQLN2-HSP70 axis reduces poly-Gly-Ala aggregates and alleviates behavioral defects in the C9ORF72 animal model

Zhang, Kejing; Wang, Ailian; Zhong, Keke; Su, Qi; Chen, Wei; Shu, Xiaoqiu; Tu, Wen-Yo; Xu, Wentao; Chen, Xia; Xiao, Yatao; Chen, Aizhong; Bai, Lei; Zhang, Jianmin; Luo, Benyan; Wang, Wenyuan; Shen, Chengyong

doi:10.1016/j.neuron.2021.04.023

Cited by 26 publications

(35 citation statements)

References 92 publications

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“…This spatial pattern is consistent with a role for UBXN6 acting as an adaptor for recruiting VCP to poly-GA aggregates that are decorated by SQSTM1, similar to its role as a VCP adaptor for aggresomes and poly-Q containing aggregates [ 68 ]. While the GFP-tag introduces lysine residues that may be directly ubiquitinated, previous studies have shown that expression of lysine-free HA-tagged poly-GA in cells leads to formation of poly-GA aggregates that are both ubiquitin- and p62-positive [ 96 , 100 ]. To exclude a tag-specific artifact, we repeated co-localization experiments using expression construct encoding 2xHA-tagged poly-GA that lacks any lysine residues and found a similar association with VCP and HSPA8 (Additional file 1 : Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…While poly-GR can recruit TDP-43 into cytoplasmic inclusions [ 14 ], poly-GA may promote TDP-43 aggregation more indirectly via inhibition of proteasome mediated protein degradation [ 41 , 73 ]. Studies in mouse models report poly-GA toxicity causing neuroinflammation and additional defects caused by the sequestration of proteins into insoluble aggregates [ 41 , 47 , 84 , 100 , 101 ]. For these reasons, interrogating poly-GA interactomes and affected pathways will contribute to a better understanding of c9FTD/ALS relevant disease processes and therapeutic targets [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…HSP70/HSC70 proteins are also regulated by their association with co-chaperones and other factors. Notably, the ALS/FTD risk factor UBQLN2 can recognize ubiquitinated HSP70 to facilitate the clearance of poly-GA aggregates, thereby alleviating neurotoxicity in a poly-GA animal model [ 100 ]. Here we found an association with the C-terminal HSC70-interacting protein (CHIP), which acts as a chaperone dependent E3 ligase that ubiquitinates unfolded proteins and can bind to HSC70 and HSP70, and can switch chaperone activity from protein folding to protein degradation [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

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Proximity proteomics of C9orf72 dipeptide repeat proteins identifies molecular chaperones as modifiers of poly-GA aggregation

Liu

Morderer

Wren

et al. 2022

acta neuropathol commun

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The most common inherited cause of two genetically and clinico-pathologically overlapping neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is the presence of expanded GGGGCC intronic hexanucleotide repeats in the C9orf72 gene. Aside from haploinsufficiency and toxic RNA foci, another non-exclusive disease mechanism is the non-canonical translation of the repeat RNA into five different dipeptide repeat proteins (DPRs), which form neuronal inclusions in affected patient brains. While evidence from cellular and animal models supports a toxic gain-of-function of pathologic poly-GA, poly-GR, and poly-PR aggregates in promoting deposition of TDP-43 pathology and neurodegeneration in affected brain areas, the relative contribution of DPRs to the disease process in c9FTD/ALS patients remains unclear. Here we have used the proximity-dependent biotin identification (BioID) proximity proteomics approach to investigate the formation and collective composition of DPR aggregates using cellular models. While interactomes of arginine rich poly-GR and poly-PR aggregates overlapped and were enriched for nucleolar and ribosomal proteins, poly-GA aggregates demonstrated a distinct association with proteasomal components, molecular chaperones (HSPA1A/HSP70, HSPA8/HSC70, VCP/p97), co-chaperones (BAG3, DNAJA1A) and other factors that regulate protein folding and degradation (SQSTM1/p62, CALR, CHIP/STUB1). Experiments in cellular models of poly-GA pathology show that molecular chaperones and co-chaperones are sequestered to the periphery of dense cytoplasmic aggregates, causing depletion from their typical cellular localization. Their involvement in the pathologic process is confirmed in autopsy brain tissue, where HSPA8, BAG3, VCP, and its adapter protein UBXN6 show a close association with poly-GA aggregates in the frontal cortex, temporal cortex, and hippocampus of c9FTLD and c9ALS cases. The association of heat shock proteins and co-chaperones with poly-GA led us to investigate their potential role in reducing its aggregation. We identified HSP40 co-chaperones of the DNAJB family as potent modifiers that increased the solubility of poly-GA, highlighting a possible novel therapeutic avenue and a central role of molecular chaperones in the pathogenesis of human C9orf72-linked diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Proximity proteomics of C9orf72 dipeptide repeat proteins identifies molecular chaperones as modifiers of poly-GA aggregation

Liu

Morderer

Wren

et al. 2022

acta neuropathol commun

View full text Add to dashboard Cite

show abstract

“…Interactions between protein aggregates and HSP70 are facilitated by UBQLN2. Previous studies show that UBQLN2 is activated by HTT or poly-GA aggregates binding to HSP70 ( Hjerpe et al, 2016 ; Zhang et al, 2021 ). This interaction is abolished in the presence of ALS/frontotemporal dementia-linked mutations in UBQLN2 or knock-down of CHIP ( Zhang et al, 2021 ).…”

Section: The Ub-proteasome System In Reversing Protein Aggregationmentioning

confidence: 98%

“…Mutations in UBQLN2 are implicated in familial ALS and have been found to decrease proteasome-mediated aggregate degradation ( Deng et al, 2011 ; Chang and Monteiro, 2015 ; Hjerpe et al, 2016 ). Interestingly, UBQLN2 appears to preferentially associate with larger protein aggregates over monomers ( Zhang et al, 2021 ). This seems consistent with the observation that deletion of dsk2 , the yeast homolog of UBQLN2 , has no effect on early HTT aggregation but was required once intracellular protein deposits of aggregated proteins known as inclusion bodies have formed ( Chuang et al, 2016 ).…”

Section: The Ub-proteasome System In Reversing Protein Aggregationmentioning

confidence: 99%

A Potential Mechanism for Targeting Aggregates With Proteasomes and Disaggregases in Liquid Droplets

Hayes

Sirvio

2022

Front. Aging Neurosci.

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Insoluble protein deposits are hallmarks of neurodegenerative disorders and common forms of dementia. The aberrant aggregation of misfolded proteins involves a complex cascade of events that occur over time, from the cellular to the clinical phase of neurodegeneration. Declining neuronal health through increased cell stress and loss of protein homeostasis (proteostasis) functions correlate with the accumulation of aggregates. On the cellular level, increasing evidence supports that misfolded proteins may undergo liquid-liquid phase separation (LLPS), which is emerging as an important process to drive protein aggregation. Studying, the reverse process of aggregate disassembly and degradation has only recently gained momentum, following reports of enzymes with distinct aggregate-disassembly activities. In this review, we will discuss how the ubiquitin-proteasome system and disaggregation machineries such as VCP/p97 and HSP70 system may disassemble and/or degrade protein aggregates. In addition to their canonically associated functions, these enzymes appear to share a common feature: reversibly assembling into liquid droplets in an LLPS-driven manner. We review the role of LLPS in enhancing the disassembly of aggregates through locally increasing the concentration of these enzymes and their co-proteins together within droplet structures. We propose that such activity may be achieved through the concerted actions of disaggregase machineries, the ubiquitin-proteasome system and their co-proteins, all of which are condensed within transient aggregate-associated droplets (TAADs), ultimately resulting in aggregate clearance. We further speculate that sustained engagement of these enzymatic activities within TAADs will be detrimental to normal cellular functions, where these activities are required. The possibility of facilitating endogenous disaggregation and degradation activities within TAADs potentially represents a novel target for therapeutic intervention to restore protein homeostasis at the early stages of neurodegeneration.

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The contribution of proteasomal impairment to autophagy activation by C9orf72 poly-GA aggregates

Tai

Yuan

et al. 2022

Cell. Mol. Life Sci.

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UBQLN2-HSP70 axis reduces poly-Gly-Ala aggregates and alleviates behavioral defects in the C9ORF72 animal model

Cited by 26 publications

References 92 publications

Proximity proteomics of C9orf72 dipeptide repeat proteins identifies molecular chaperones as modifiers of poly-GA aggregation

Proximity proteomics of C9orf72 dipeptide repeat proteins identifies molecular chaperones as modifiers of poly-GA aggregation

A Potential Mechanism for Targeting Aggregates With Proteasomes and Disaggregases in Liquid Droplets

The contribution of proteasomal impairment to autophagy activation by C9orf72 poly-GA aggregates

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