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; Raković, Aleksandar; Lohmann, Katja; Dulovic-Mahlow, Marija

doi:10.3390/ijms23179524

Cited by 17 publications

(9 citation statements)

References 46 publications

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“…A widely acknowledged hypothesis regarding the 'atypical form' of parkinsonism, an emerging important feature of these disorders, with its rapid progression and cognitive decline is that massive protein and organellar accumulation may lead to excessive neuronal waste and degeneration 63 . Previous reports identified autophagopathies such as WDR45 defects as the cause of both childhood NDD 46 and early adulthood parkinsonism 64 , suggesting substantial clinico-pathological overlap reflective of the molecular interactions between EPG5 and WDR45 in the autophagosome-lysosome fusion machinery (Figure 6). The autophagosome-lysosome fusion machinery is rapidly emerging as a hotspot for neurological disease, with pathogenic variants also in SNAP29, RAB7A, and HOPS complex components implicated in a wide range of neurological diseases [65][66][67][68] , highlighting a promising target for future investigations.…”

Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 90%

Mutations in EPG5 are associated with a wide spectrum of neurodevelopmental and neurodegenerative disorders

Dafsari,

Deneubourg,

Singh

et al. 2024

Preprint

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Autophagy is a fundamental and evolutionary conserved biological pathway with vital roles in intracellular quality control and homeostasis. The process of autophagy involves the engulfment of intracellular targets by autophagosomes and their delivery to the lysosome for digestion and recycling. We have previously reported recessive variants inEPG5, encoding for the ectopic P-granules 5 autophagy protein with a crucial role in autophagosome-lysosome fusion, as the cause of Vici syndrome (VS), a severe multisystem neurodevelopmental disorder defined by a combination of distinct clinical features including callosal agenesis, cataracts, cardiomyopathy, immunodeficiency, and hypopigmentation. Here, we present extensive novel genetic, clinical, neuroradiological and pathological features from the largest cohort ofEPG5-related disorders reported to date, complemented by experimental findings from patient cells and models of EPG5 defects inCaenorhabditis elegansandMus musculus. We identified 200 patients with recessiveEPG5variants, 86 of them previously unpublished. The associated phenotypic spectrum ranged from antenatally lethal presentations and the classic VS phenotype (n=60) to much milder neurodevelopmental disorders with less specific manifestations (n=140). Myopathic features and epilepsy with variable progression were frequently observed. Novel manifestations included early-onset parkinsonism and dystonia with cognitive decline during adolescence, hereditary spastic paraplegia (HSPP), and myoclonus. Radiological findings included previously recognizedEPG5-related features with callosal abnormalities and pontocerebellar hypoplasia, and a range of novel features suggesting an emerging continuum with disorders of brain iron accumulation or copper metabolism as well as HSPPs. Genotype-phenotype studies suggested a correlation between predicted residual EPG5 expression and clinical severity, especially regarding disease progression and survival. The Epg5 p.Gln331Arg knock-in mouse, a model of milderEPG5-related disorders, showed an age-related motor phenotype and impaired autophagic clearance in several brain regions mirroring those also affected in humans. InCaenorhabditis elegans, epg-5knockdown gave rise to neurodevelopmental features and motor impairment comparable to defects in parkinsonism-related genes, abnormal mitochondrial respiration, and impaired mitophagic clearance early in life. Cellular assays revealed impaired PINK1-Parkin dependent mitophagic clearance in patient fibroblasts. Our findings expand the phenotypic spectrum ofEPG5-related disorders and indicate a life time continuum of disease that overlaps with other disorders of defective autophagy and intracellular trafficking. Our observations also suggest close links between early-onset neurodevelopmental and neurodegenerative conditions of later onset due to EPG5 defects, in particular dystonia and parkinsonism, highlighting the fundamental importance of dysfunctional autophagy in the pathophysiology of common neurodegenerative disorders.

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Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 90%

Mutations in EPG5 are associated with a wide spectrum of neurodevelopmental and neurodegenerative disorders

Dafsari,

Deneubourg,

Singh

et al. 2024

Preprint

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“…While we were working on this project, other studies suggested that WDR45 depletion causes ferroptosis [29][30][31] . However, these reports, which were cell-culture based, suggested that the ferroptosis was due to defective autophagy-dependent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Loss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis

Zhu,

Fujimaki,

Snape

et al. 2024

Nat Cell Biol

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Abstractβ-Propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant disease, one of several conditions that manifest with neurodegeneration and brain iron accumulation. Mutations in the WD repeat domain 45 (WDR45) gene encoding WIPI4 lead to loss of function in BPAN but the cellular mechanisms of how these trigger pathology are unclear. The prevailing view in the literature is that BPAN is simply the consequence of autophagy deficiency given that WIPI4 functions in this degradation pathway. However, our data indicate that WIPI4 depletion causes ferroptosis—a type of cell death induced by lipid peroxidation—via an autophagy-independent mechanism, as demonstrated both in cell culture and in zebrafish. WIPI4 depletion increases ATG2A localization at endoplasmic reticulum–mitochondrial contact sites, which enhances phosphatidylserine import into mitochondria. This results in increased mitochondrial synthesis of phosphatidylethanolamine, a major lipid prone to peroxidation, thus enabling ferroptosis. This mechanism has minimal overlap with classical ferroptosis stimuli but provides insights into the causes of neurodegeneration in BPAN and may provide clues for therapeutic strategies.

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“…The mitochondrial network was investigated as previously described [ 21 , 22 ]. Cells were either stained under basal conditions or after treatment with paraquat (2 mM) for 5 h. Subsequently, the mitochondrial network in the fibroblasts was stained with an anti-GRP75 antibody (1:1000, Abcam, Cambridge, MA, USA) in combination with the Zenon immunolabelling kit (Invitrogen, Carlsbad, CA, USA) according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant

Pauly

Korenke

Diaw

et al. 2023

Genes

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Biallelic variants in the mitochondrial form of the tryptophanyl-tRNA synthetases (WARS2) can cause a neurodevelopmental disorder with movement disorders including early-onset tremor–parkinsonism syndrome. Here, we describe four new patients, who all presented at a young age with a tremor–parkinsonism syndrome and responded well to levodopa. All patients carry the same recurrent, hypomorphic missense variant (NM_015836.4: c.37T>G; p.Trp13Gly) either together with a previously described truncating variant (NM_015836.4: c.797Cdel; p.Pro266ArgfsTer10), a novel truncating variant (NM_015836.4: c.346C>T; p.Gln116Ter), a novel canonical splice site variant (NM_015836.4: c.349-1G>A), or a novel missense variant (NM_015836.4: c.475A>C, p.Thr159Pro). We investigated the mitochondrial function in patients and found increased levels of mitochondrially encoded cytochrome C Oxidase II as part of the mitochondrial respiratory chain as well as decreased mitochondrial integrity and branching. Finally, we conducted a literature review and here summarize the broad phenotypical spectrum of reported WARS2-related disorders. In conclusion, WARS2-related disorders are diagnostically challenging diseases due to the broad phenotypic spectrum and the disease relevance of a relatively common missense change that is often filtered out in a diagnostic setting since it occurs in ~0.5% of the general European population.

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Mutant WDR45 Leads to Altered Ferritinophagy and Ferroptosis in β-Propeller Protein-Associated Neurodegeneration

Cited by 17 publications

References 46 publications

Mutations in EPG5 are associated with a wide spectrum of neurodevelopmental and neurodegenerative disorders

Mutations in EPG5 are associated with a wide spectrum of neurodevelopmental and neurodegenerative disorders

Loss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis

The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant

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