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Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells

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Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells. / Seibler, Philip; Burbulla, Lena F; Dulovic, Marija; Zittel, Simone; Heine, Johanne; Schmidt, Thomas; Rudolph, Franziska; Westenberger, Ana; Rakovic, Aleksandar; Münchau, Alexander; Krainc, Dimitri; Klein, Christine.

in: BRAIN, Jahrgang 141, Nr. 10, 01.10.2018, S. 3052-3064.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Seibler, P, Burbulla, LF, Dulovic, M, Zittel, S, Heine, J, Schmidt, T, Rudolph, F, Westenberger, A, Rakovic, A, Münchau, A, Krainc, D & Klein, C 2018, 'Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells', BRAIN, Jg. 141, Nr. 10, S. 3052-3064. https://doi.org/10.1093/brain/awy230

APA

Seibler, P., Burbulla, L. F., Dulovic, M., Zittel, S., Heine, J., Schmidt, T., Rudolph, F., Westenberger, A., Rakovic, A., Münchau, A., Krainc, D., & Klein, C. (2018). Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells. BRAIN, 141(10), 3052-3064. https://doi.org/10.1093/brain/awy230

Vancouver

Seibler P, Burbulla LF, Dulovic M, Zittel S, Heine J, Schmidt T et al. Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells. BRAIN. 2018 Okt 1;141(10):3052-3064. https://doi.org/10.1093/brain/awy230

Bibtex

@article{ce6ebb0dd1844b4b8733de2b857cbac4,
title = "Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells",
abstract = "Beta-propeller protein-associated neurodegeneration is a subtype of monogenic neurodegeneration with brain iron accumulation caused by de novo mutations in WDR45. The WDR45 protein functions as a beta-propeller scaffold and plays a putative role in autophagy through its interaction with phospholipids and autophagy-related proteins. Loss of WDR45 function due to disease-causing mutations has been linked to defects in autophagic flux in patient and animal cells. However, the role of WDR45 in iron homeostasis remains elusive. Here we studied patient-specific WDR45 mutant fibroblasts and induced pluripotent stem cell-derived midbrain neurons. Our data demonstrated that loss of WDR45 increased cellular iron levels and oxidative stress, accompanied by mitochondrial abnormalities, autophagic defects, and diminished lysosomal function. Restoring WDR45 levels partially rescued oxidative stress and the susceptibility to iron treatment, and activation of autophagy reduced the observed iron overload in WDR45 mutant cells. Our data suggest that iron-containing macromolecules and organelles cannot effectively be degraded through the lysosomal pathway due to loss of WDR45 function.",
keywords = "Journal Article",
author = "Philip Seibler and Burbulla, {Lena F} and Marija Dulovic and Simone Zittel and Johanne Heine and Thomas Schmidt and Franziska Rudolph and Ana Westenberger and Aleksandar Rakovic and Alexander M{\"u}nchau and Dimitri Krainc and Christine Klein",
year = "2018",
month = oct,
day = "1",
doi = "10.1093/brain/awy230",
language = "English",
volume = "141",
pages = "3052--3064",
journal = "BRAIN",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "10",

}

RIS

TY - JOUR

T1 - Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells

AU - Seibler, Philip

AU - Burbulla, Lena F

AU - Dulovic, Marija

AU - Zittel, Simone

AU - Heine, Johanne

AU - Schmidt, Thomas

AU - Rudolph, Franziska

AU - Westenberger, Ana

AU - Rakovic, Aleksandar

AU - Münchau, Alexander

AU - Krainc, Dimitri

AU - Klein, Christine

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Beta-propeller protein-associated neurodegeneration is a subtype of monogenic neurodegeneration with brain iron accumulation caused by de novo mutations in WDR45. The WDR45 protein functions as a beta-propeller scaffold and plays a putative role in autophagy through its interaction with phospholipids and autophagy-related proteins. Loss of WDR45 function due to disease-causing mutations has been linked to defects in autophagic flux in patient and animal cells. However, the role of WDR45 in iron homeostasis remains elusive. Here we studied patient-specific WDR45 mutant fibroblasts and induced pluripotent stem cell-derived midbrain neurons. Our data demonstrated that loss of WDR45 increased cellular iron levels and oxidative stress, accompanied by mitochondrial abnormalities, autophagic defects, and diminished lysosomal function. Restoring WDR45 levels partially rescued oxidative stress and the susceptibility to iron treatment, and activation of autophagy reduced the observed iron overload in WDR45 mutant cells. Our data suggest that iron-containing macromolecules and organelles cannot effectively be degraded through the lysosomal pathway due to loss of WDR45 function.

AB - Beta-propeller protein-associated neurodegeneration is a subtype of monogenic neurodegeneration with brain iron accumulation caused by de novo mutations in WDR45. The WDR45 protein functions as a beta-propeller scaffold and plays a putative role in autophagy through its interaction with phospholipids and autophagy-related proteins. Loss of WDR45 function due to disease-causing mutations has been linked to defects in autophagic flux in patient and animal cells. However, the role of WDR45 in iron homeostasis remains elusive. Here we studied patient-specific WDR45 mutant fibroblasts and induced pluripotent stem cell-derived midbrain neurons. Our data demonstrated that loss of WDR45 increased cellular iron levels and oxidative stress, accompanied by mitochondrial abnormalities, autophagic defects, and diminished lysosomal function. Restoring WDR45 levels partially rescued oxidative stress and the susceptibility to iron treatment, and activation of autophagy reduced the observed iron overload in WDR45 mutant cells. Our data suggest that iron-containing macromolecules and organelles cannot effectively be degraded through the lysosomal pathway due to loss of WDR45 function.

KW - Journal Article

U2 - 10.1093/brain/awy230

DO - 10.1093/brain/awy230

M3 - SCORING: Journal article

C2 - 30169597

VL - 141

SP - 3052

EP - 3064

JO - BRAIN

JF - BRAIN

SN - 0006-8950

IS - 10

ER -