DNAJB6, a Key Factor in Neuronal Sensitivity to Amyloidogenesis

Thiruvalluvan, Arun; Mattos, Eduardo Preusser de; Brunsting, Jeanette F.; Bakels, Rob; Serlidaki, Despina; Barazzuol, Lara; Conforti, Paola; Fatima, Azra; Koyuncu, Seda; Cattaneo, Elena; Vı́lchez, David; Bergink, Steven; Boddeke, Erik; Copray, Sjef; Kampinga, Harm H.

doi:10.1016/j.molcel.2020.02.022

Cited by 60 publications

(70 citation statements)

References 95 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For DNAJB6 and DNAJB8, the suppression of Fluc DM aggregation not only appears mechanistically different from DNAJB1, but is also distinct from what has been reported previously for the handling of amyloid-fibril forming proteins, such as polyQ-expanded proteins and the amyloid-β peptide (Hageman et al, 2010;Kakkar et al, 2016b;Månsson et al, 2018). Whilst the S/T-rich region and, to some extent, the G/F-rich region (Sarparanta et al, 2012;Thiruvalluvan et al, 2020) in DNAJB6 and DNAJB8 are essential for amyloid suppression, these regions are not required to inhibit Fluc DM inclusion formation. Finally, we identified a short, 23 amino acid (TTK-LKS) sequence in the C-terminus of DNAJB8 that is required to inhibit Fluc DM inclusion formation even though it is was found to be dispensable for suppression of polyQ aggregation (Hageman et al, 2010).…”

Section: Discussionmentioning

confidence: 60%

“…mutations have been associated with limb-girdle muscular dystrophy and it has been suggested that these mutations lead to disruption of the J to G/F-interdomain interaction and minor loss of function in their capacity to suppress polyQ aggregation (Sarparanta et al, 2012;Thiruvalluvan et al, 2020). However, we found that both the F93L and P96R mutational variants of DNAJB6 fully retained the ability to inhibit the aggregation of destabilised Fluc DM into inclusions (Fig.…”

mentioning

confidence: 63%

“…Plasmids encoding mutations (M1-4) in the S/T-rich region of DNAJB6 are previously described by Kakkar et al (2016b) whilst constructs expressing disease-related missense mutations (F93L and P96R) in the G/F-rich region are described by Thiruvalluvan et al (2020).…”

Section: Plasmid Constructsmentioning

confidence: 99%

See 2 more Smart Citations

DNAJB chaperones inhibit aggregation of destabilised proteins via a C-terminal region distinct from that used to prevent amyloid formation

McMahon

Bergink

Kampinga

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Disturbances to protein homeostasis (proteostasis) can lead to protein aggregation and inclusion formation, processes associated with a variety of neurodegenerative disorders. DNAJBs are molecular chaperones previously identified as potent suppressors of disease-related protein aggregation. In this work, we over-expressed a destabilised isoform of firefly luciferase (R188Q/R261Q Fluc; FlucDM) in cells to assess the capacity of DNAJBs to inhibit inclusion formation. Co-expression of all DNAJBs tested significantly inhibited the intracellular aggregation of FlucDM. Moreover, we show that DNAJBs suppress aggregation by supporting the Hsp70-dependent degradation of FlucDM via the proteasome. The serine-rich stretch in DNAJB6 and DNAJB8, essential for preventing fibrillar aggregation, is not involved in the suppression of FlucDM inclusion formation. Conversely, deletion of the C-terminal TTK-LKS region in DNAJB8, a region not required to suppress polyQ aggregation, abolished its ability to inhibit inclusion formation by FlucDM. Thus, our data suggest that DNAJB6 and DNAJB8 possess two distinct domains involved in the inhibition of protein aggregation, one responsible for binding to β-hairpins that form during amyloid formation and another that mediates the degradation of destabilised client proteins via the proteasome.Summary statementSpecialised DNAJB molecular chaperones are potent suppressors of protein aggregation and interact with different types of client proteins via distinct C-terminal regions

show abstract

Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 63%

See 1 more Smart Citation

DNAJB chaperones inhibit aggregation of destabilised proteins via a C-terminal region distinct from that used to prevent amyloid formation

McMahon

Bergink

Kampinga

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…DNAJB6 emerges as a key protective co-chaperone for polyQ containing sequences and has been shown to very efficiently inhibit the primary nucleation step in polyQ amyloid formation by directly binding to the polyQ tract (Gillis et al, 2013 ; Kakkar et al, 2016 ). Moreover, recent research revealed that during differentiation of pluripotent stem cell lines from HD patients into neurons, there is a loss of expression in DNAJB6, which leads to aggregation of polyQ (Thiruvalluvan et al, 2020 ). This could explain why pathological aggregates are predominantly present in neurons and why stem cells are protected.…”

Section: The Role Of Chaperones In Prion-like Propagationmentioning

confidence: 99%

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

Tittelmeier

Nachman

Nussbaum-Krammer

2020

Front. Aging Neurosci.

View full text Add to dashboard Cite

Aberrant accumulation of misfolded proteins into amyloid deposits is a hallmark in many age-related neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Pathological inclusions and the associated toxicity appear to spread through the nervous system in a characteristic pattern during the disease. This has been attributed to a prion-like behavior of amyloid-type aggregates, which involves self-replication of the pathological conformation, intercellular transfer, and the subsequent seeding of native forms of the same protein in the neighboring cell. Molecular chaperones play a major role in maintaining cellular proteostasis by assisting the (re)-folding of cellular proteins to ensure their function or by promoting the degradation of terminally misfolded proteins to prevent damage. With increasing age, however, the capacity of this proteostasis network tends to decrease, which enables the manifestation of neurodegenerative diseases. Recently, there has been a plethora of studies investigating how and when chaperones interact with disease-related proteins, which have advanced our understanding of the role of chaperones in protein misfolding diseases. This review article focuses on the steps of prion-like propagation from initial misfolding and self-templated replication to intercellular spreading and discusses the influence that chaperones have on these various steps, highlighting both the positive and adverse consequences chaperone action can have. Understanding how chaperones alleviate and aggravate disease progression is vital for the development of therapeutic strategies to combat these debilitating diseases.

show abstract

“…Generation of iPSCs derived from patients with spinocerebellar ataxia class 3 was described previously (109). Human dermal fibroblasts (HDFs) were cultured in…”

Section: Generation Of Ipscs Of Sca-3 Patients With Episomal Vectorsmentioning

confidence: 99%

Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates

García-Huerta

Troncoso-Escudero

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

One sentence summary: IGF2 reduces the load of intracellular protein aggregates through the extracellular disposal of the mutant protein. AbstractImpaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various models of neurodegeneration. To identify disease-modifier genes that may explain the neuroprotective effects of XBP1 deficiency, we performed gene expression profiling of brain cortex and striatum of these animals and uncovered insulin-like growth factor 2 (Igf2) as the major upregulated gene. Here we studied the impact of IGF2 signaling on protein aggregation in models of Huntington´s disease (HD) as proof-of-concept. Cell culture studies revealed that IGF2 treatment decreases the load of intracellular aggregates of mutant huntingtin and a polyglutamine peptide. These results were validated using induced pluripotent stem cells (iPSC)-derived medium spiny neurons from HD patients.The reduction in the levels of mutant huntingtin was associated with a decrease in the half-life of the intracellular protein. The decrease in the levels of abnormal protein aggregation triggered by IGF2 were independent of the activity of autophagy and the proteasome pathways, the two main routes for mutant huntingtin clearance. Conversely, IGF2 signaling enhanced the secretion of soluble mutant huntingtin species through exosomes and microvesicles involving changes in actin dynamics. Administration of IGF2 into the brain of HD mice using gene therapy led to a significant decrease in the levels of mutant huntingtin in three different animal models. Moreover, analysis of human post-mortem brain tissue, and blood samples from HD patients showed a reduction of IGF2 level. This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of abnormal protein aggregates. tools to study IGF2 signaling. We thank Marioly Müller and Dr. Josefina Barrera and her team for their kind help taking the blood samples. We thank Dr. Felipe Oyarzun and Rodrigo Sierpe for the kindly help with the use of the Nanosight NS300. We specially acknowledge Carolina Jerez, Claudia Rivera, Valentina Castillo and Constanza Gonzalez for their technical assistance.

show abstract

DNAJB6, a Key Factor in Neuronal Sensitivity to Amyloidogenesis

Cited by 60 publications

References 95 publications

DNAJB chaperones inhibit aggregation of destabilised proteins via a C-terminal region distinct from that used to prevent amyloid formation

DNAJB chaperones inhibit aggregation of destabilised proteins via a C-terminal region distinct from that used to prevent amyloid formation

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates

Contact Info

Product

Resources

About