Mutant WDR45 Leads to Altered Ferritinophagy and Ferroptosis in β-Propeller Protein-Associated Neurodegeneration
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Mutant WDR45 Leads to Altered Ferritinophagy and Ferroptosis in β-Propeller Protein-Associated Neurodegeneration. / Diaw, Sokhna Haissatou; Ganos, Christos; Zittel, Simone; Plötze-Martin, Kirstin; Kulikovskaja, Leonora; Vos, Melissa; Westenberger, Ana; Rakovic, Aleksandar; Lohmann, Katja; Dulovic-Mahlow, Marija.
In: INT J MOL SCI, Vol. 23, No. 17, 9524, 23.08.2022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Mutant WDR45 Leads to Altered Ferritinophagy and Ferroptosis in β-Propeller Protein-Associated Neurodegeneration
AU - Diaw, Sokhna Haissatou
AU - Ganos, Christos
AU - Zittel, Simone
AU - Plötze-Martin, Kirstin
AU - Kulikovskaja, Leonora
AU - Vos, Melissa
AU - Westenberger, Ana
AU - Rakovic, Aleksandar
AU - Lohmann, Katja
AU - Dulovic-Mahlow, Marija
PY - 2022/8/23
Y1 - 2022/8/23
N2 - Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) caused by loss-of-function variants in WDR45. The underlying mechanism of iron accumulation in WDR45 deficiency remains elusive. We established a primary skin fibroblast culture of a new BPAN patient with a missense variant p.(Asn61Lys) in WDR45 (NM_007075.3: c.183C>A). The female patient has generalized dystonia, anarthria, parkinsonism, spasticity, stereotypies, and a distinctive cranial MRI with generalized brain atrophy, predominantly of the cerebellum. For the functional characterization of this variant and to provide a molecular link of WDR45 and iron accumulation, we looked for disease- and variant-related changes in the patient’s fibroblasts by qPCR, immunoblotting and immunofluorescence comparing to three controls and a previously reported WDR45 patient. We demonstrated molecular changes in mutant cells comprising an impaired mitochondrial network, decreased levels of lysosomal proteins and enzymes, and altered autophagy, confirming the pathogenicity of the variant. Compared to increased levels of the ferritinophagy marker Nuclear Coactivator 4 (NCOA4) in control cells upon iron treatment, patients’ cells revealed unchanged NCOA4 protein levels, indicating disturbed ferritinophagy. Additionally, we observed abnormal protein levels of markers of the iron-dependent cell death ferroptosis in patients’ cells. Altogether, our data suggests that WDR45 deficiency affects ferritinophagy and ferroptosis, consequentially disturbing iron recycling.
AB - Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) caused by loss-of-function variants in WDR45. The underlying mechanism of iron accumulation in WDR45 deficiency remains elusive. We established a primary skin fibroblast culture of a new BPAN patient with a missense variant p.(Asn61Lys) in WDR45 (NM_007075.3: c.183C>A). The female patient has generalized dystonia, anarthria, parkinsonism, spasticity, stereotypies, and a distinctive cranial MRI with generalized brain atrophy, predominantly of the cerebellum. For the functional characterization of this variant and to provide a molecular link of WDR45 and iron accumulation, we looked for disease- and variant-related changes in the patient’s fibroblasts by qPCR, immunoblotting and immunofluorescence comparing to three controls and a previously reported WDR45 patient. We demonstrated molecular changes in mutant cells comprising an impaired mitochondrial network, decreased levels of lysosomal proteins and enzymes, and altered autophagy, confirming the pathogenicity of the variant. Compared to increased levels of the ferritinophagy marker Nuclear Coactivator 4 (NCOA4) in control cells upon iron treatment, patients’ cells revealed unchanged NCOA4 protein levels, indicating disturbed ferritinophagy. Additionally, we observed abnormal protein levels of markers of the iron-dependent cell death ferroptosis in patients’ cells. Altogether, our data suggests that WDR45 deficiency affects ferritinophagy and ferroptosis, consequentially disturbing iron recycling.
KW - Autophagy/genetics
KW - Brain/metabolism
KW - Carrier Proteins/genetics
KW - Female
KW - Ferroptosis/genetics
KW - Humans
KW - Iron/metabolism
KW - Magnetic Resonance Imaging
KW - Neurodegenerative Diseases/genetics
U2 - 10.3390/ijms23179524
DO - 10.3390/ijms23179524
M3 - SCORING: Journal article
C2 - 36076926
VL - 23
JO - INT J MOL SCI
JF - INT J MOL SCI
SN - 1661-6596
IS - 17
M1 - 9524
ER -