Thiruvalluvan, Arun, de Mattos, Eduardo P., Brunsting, Jeanette F., Bakels, Rob, Serlidaki, Despina, Barazzuol, Lara, Conforti, Paola, Fatima, Azra, Koyuncu, Seda, Cattaneo, Elena, Vilchez, David, Bergink, Steven, Boddeke, Erik H. W. G., Copray, Sjef and Kampinga, Harm H. (2020). DNAJB6, a Key Factor in Neuronal Sensitivity to Amyloidogenesis. Mol. Cell, 78 (2). S. 346 - 368. CAMBRIDGE: CELL PRESS. ISSN 1097-4164

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Abstract

CAG-repeat expansions in at least eight different genes cause neurodegeneration. The length of the extended polyglutamine stretches in the corresponding proteins is proportionally related to their aggregation propensity. Although these proteins are ubiquitously expressed, they predominantly cause toxicity to neurons. To understand this neuronal hypersensitivity, we generated induced pluripotent stem cell (iPSC) lines of spinocerebellar ataxia type 3 and Huntington's disease patients. iPSC generation and neuronal differentiation are unaffected by polyglutamine proteins and show no spontaneous aggregate formation. However, upon glutamate treatment, aggregates form in neurons but not in patient-derived neural progenitors. During differentiation, the chaperone network is drastically rewired, including loss of expression of the antiamyloidogenic chaperone DNAJB6. Upregulation of DNAJB6 in neurons antagonizes glutamate-induced aggregation, while knockdown of DNAJB6 in progenitors results in spontaneous polyglutamine aggregation. Loss of DNAJB6 expression upon differentiation is confirmed in vivo, explaining why stem cells are intrinsically protected against amyloidogenesis and protein aggregates are dominantly present in neurons.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Thiruvalluvan, ArunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Mattos, Eduardo P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunsting, Jeanette F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bakels, RobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serlidaki, DespinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barazzuol, LaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Conforti, PaolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fatima, AzraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koyuncu, SedaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cattaneo, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vilchez, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bergink, StevenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boddeke, Erik H. W. G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Copray, SjefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kampinga, Harm H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-336935
DOI: 10.1016/j.molcel.2020.02.022
Journal or Publication Title: Mol. Cell
Volume: 78
Number: 2
Page Range: S. 346 - 368
Date: 2020
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4164
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HEAT-SHOCK PROTEINS; POLYGLUTAMINE AGGREGATION; HUNTINGTONS-DISEASE; ASYMMETRIC INHERITANCE; MOLECULAR CHAPERONES; ANDROGEN RECEPTOR; DAMAGED PROTEINS; RICH REGION; CELL LINES; MUTATIONSMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33693

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