The Molecular Chaperone DNAJB6, but Not DNAJB1, Suppresses the Seeded Aggregation of Alpha-Synuclein in Cells

Arkan, Sertan; Hansen, Christian

doi:10.3390/ijms20184495

Cited by 29 publications

(29 citation statements)

References 42 publications

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“…The antiaggregation effect of DNAJB6b on α-synuclein in cells and in vitro was shown to be HSPAand JD-dependent and largely independent of the hydroxyl groups of the S/T region [61]. Very recently, further studies confirmed the increased susceptibility of DNAJB6-deficient cells to seeded α-synuclein aggregation and suggested that DNAJB6 promotes proteasomal turnover of α-synuclein [52].…”

Section: Antiaggregation and Cytoprotectionmentioning

confidence: 93%

“…Interactions with other BAG proteins in addition to BAG3 [2] are compatible with the idea that DNAJB6 has cochaperone functions related to multiple pathways. Some experimental evidence indicates that DNAJB6 may promote proteasomal degradation of clients [30,52], and this is supported by its interaction with the proteasome subunit PSMD2 [2].…”

Section: Cochaperone Functionmentioning

confidence: 99%

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Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Sarparanta

Jonson

Kawan

et al. 2020

IJMS

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Skeletal muscle and the nervous system depend on efficient protein quality control, and they express chaperones and cochaperones at high levels to maintain protein homeostasis. Mutations in many of these proteins cause neuromuscular diseases, myopathies, and hereditary motor and sensorimotor neuropathies. In this review, we cover mutations in DNAJB6, DNAJB2, αB-crystallin (CRYAB, HSPB5), HSPB1, HSPB3, HSPB8, and BAG3, and discuss the molecular mechanisms by which they cause neuromuscular disease. In addition, previously unpublished results are presented, showing downstream effects of BAG3 p.P209L on DNAJB6 turnover and localization.

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Section: Antiaggregation and Cytoprotectionmentioning

confidence: 93%

Section: Cochaperone Functionmentioning

confidence: 99%

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Sarparanta

Jonson

Kawan

et al. 2020

IJMS

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“…Several DNAJ proteins are linked to PD, and a role for DNAJB6, a member of this family in the suppression of α-synuclein aggregation and proteasomal degradation, has been reported [ 83 ]. Knockout of DNAJB6 in HEK239 cells resulted in increased aggregation of α-synuclein [ 83 ]. Interestingly, this induced aggregation was abolished upon treatment of the cells with a proteasomal inhibitor (MG132) [ 83 ].…”

Section: α-Synuclein: Folding Higher-order Structures and Degradamentioning

confidence: 99%

“…Knockout of DNAJB6 in HEK239 cells resulted in increased aggregation of α-synuclein [ 83 ]. Interestingly, this induced aggregation was abolished upon treatment of the cells with a proteasomal inhibitor (MG132) [ 83 ].…”

Section: α-Synuclein: Folding Higher-order Structures and Degradamentioning

confidence: 99%

Chaperones and Proteostasis: Role in Parkinson’s Disease

2020

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Proper folding to attain a defined three-dimensional structure is a prerequisite for the functionality of a protein. Improper folding that eventually leads to formation of protein aggregates is a hallmark of several neurodegenerative disorders. Loss of protein homeostasis triggered by cellular stress conditions is a major contributing factor for the formation of these toxic aggregates. A conserved class of proteins called chaperones and co-chaperones is implicated in maintaining the cellular protein homeostasis. Expanding the body of evidence highlights the role of chaperones as central mediators in the formation, de-aggregation and degradation of the aggregates. Altered expression and function of chaperones is associated with many neurodegenerative diseases including Parkinson’s disease. Several studies indicate that chaperones are at the center of the cause and effect cycle of this disease. An overview of the various chaperones that are associated with homeostasis of Parkinson’s disease-related proteins and their role in pathogenicity will be discussed in this review.

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“…We have previously shown that α-syn PFF seeded α-syn aggregation was increased in a HEK293 cell line, stably expressing α-syn-CFP and α-syn-YFP (hereafter named α-syn FRET cells), when DNAJB6 was knocked out (20). Here, we examined if overexpression of DNAJB6 would suppress α-syn aggregation induced by PFF's in the same cell line set up, and observed that overexpression of DNAJB6 decreased the seeded α-syn aggregation more than 4-fold ( Figure 1A and B).…”

Section: Overexpression Of Dnajb6 Is Protect Against α-Syn Aggregatiomentioning

confidence: 99%

DNAJB6 Suppresses Alpha-synuclein Induced Pathology in an Animal Model of Parkinson’s Disease

Arkan

Ljungberg

Kirik

et al. 2020

Preprint

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Background: α-synuclein (α-syn) aggregation can lead to degeneration of dopaminergic neurons in the substantia nigra pars compacta ( SNpc ) as invariably observed in patients with Parkinson’s Disease (PD). The co-chaperone DNAJB6 has previously been found to be expressed at higher levels in PD patients than in control subjects and was also found in Lewy bodies. Our previous experiments showed that knock out of DNAJB6 induced α-syn aggregation in cellular level. However, effects of overexpression of DNAJB6 against α-syn aggregation remains to be investigated. Methods: we used to α-syn CFP/YFP HEK293 FRET cell line to investigate the effects of overexpression of DNAJB6 in cellular level. α-syn aggregation was induced by transfection α-syn preformed fibrils (PPF), then was measured FRET analysis. We proceeded to investigate if DNAJB6b can impair α-syn aggregation and toxicity in an animal model and used adeno associated vira (AAV6) designed to overexpress of human wt α-syn, GFP-DNAJB6 or GFP in rats. These vectors were injected into the SNpc of the rats, unilaterally. Rats injected with vira to express α-syn along with GFP in the SNpc where compared to rats expressing α-syn and GFP-DNAJB6. We evaluated motor functions, dopaminergic cell death, phosphorylated α-syn in SNpc and axonal degeneration in striatum. Results : We show that DNAJB6 prevent α-syn aggregation induced by α-syn PFF’s, in a cell culture model. Also, we observed α-syn overexpression caused dopaminergic cell death and that this was strongly reduced by co-expression of DNAJB6b. In addition, the lesion caused by α-syn overexpression resulted in behavior deficits, which increased over time as seen in stepping test, which was rescued by co-expression of DNAJB6b. Moreover, we observed an increase in serine 129 (S129) phosphorylated α-syn in SNpc of rats overexpressing α-syn, that was lowered by DNAJB6 co-expression. Conclusion : We here demonstrate for the first time that DNAJB6 is a strong suppressor of α-syn aggregation in cells and in animals and that this results in a suppression of dopaminergic cell death and PD related motor deficits in an animal model of PD. Keywords: Protein homeostasis, Parkinson`s Disease, Alpha-synuclein, Adeno Associated Virus, DNAJB6, Heat Shock Protein 70

show abstract

The Molecular Chaperone DNAJB6, but Not DNAJB1, Suppresses the Seeded Aggregation of Alpha-Synuclein in Cells

Cited by 29 publications

References 42 publications

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Chaperones and Proteostasis: Role in Parkinson’s Disease

DNAJB6 Suppresses Alpha-synuclein Induced Pathology in an Animal Model of Parkinson’s Disease

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