AAV-Mediated Gene Transfer of WDR45 Corrects Neurological Deficits in the Mouse Model of Beta-Propeller Protein-Associated Neurodegeneration

Human Gene Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Beta-propeller protein-associated neurodegeneration (BPAN) is an ultra-rare, X-linked dominant, neurodevelopmental, and neurodegenerative disease caused by loss-of-function mutations in the WDR45 gene. It manifests neurodevelopmental delay seizures followed secondary neurological decline with dystonia/parkinsonism dementia adolescence early adulthood characterized progressive accumulation of iron basal ganglia. encodes β-propeller-shaped scaffold protein, or WD repeat domain phosphoinositide-interacting protein 4 (WIPI4), which plays important role autophagosome formation. While mechanisms how WIPI4 loss function results brain pathology have not yet been established, findings lower autophagic activity provide a direct link between impaired autophagy BPAN. Here we performed phenotypical characterization novel mouse model BPAN, Wdr45_ex9+1g>a mouse. We identified hyperactive behavior reduction markers tissue hemizygous males as at 2 months age. Given onset spectrum symptoms such hyper-arousal attention deficits human patients, this presents disease-relevant phenotype can be used preclinical studies. for proof-of-concept study to evaluate whether adeno-associated virus (AAV)-mediated central nervous system (CNS)-targeted gene transfer therapeutic benefit considered paradigm observed successful expression transcripts tissue, rescue behavior, correction markers. These data demonstrate that promising strategy

Language: Английский

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Mutation in Wdr45 leads to early motor dysfunction and widespread aberrant axon terminals in a beta-propeller protein associated neurodegeneration (BPAN) patient-inspired mouse model

Frontiers in Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: Feb. 28, 2025

Beta-propeller Protein Associated Neurodegeneration (BPAN) is a devastating neurodevelopmental and neurodegenerative disease linked to variants in WDR45 . Currently, there no cure or altering treatment for this disease. This is, part, due lack of insight into early phenotypes BPAN progression ’s role establishing maintaining neurological function. Here we generated characterized mouse model bearing c52C > T patient variant Wdr45. We show mutation ablates protein expression alters autophagy the brain. Behavioral analysis these mice revealed characteristic signs including cognitive impairment, hyperactivity, motor decline. behaviors coincide with widespread glial activation development axonal spheroids multiple neuron subclasses throughout Several lines evidence suggest arise from axon terminals. Transcriptomic uncovered disrupted pathways cortex genes associated synapses, neurites, endosomes, endoplasmic reticulum, ferroptosis. supported by accumulation iron regulating transferrin receptor 1 (TFRC) reticulum resident calreticulin (CALR) as animals age. CALR forms spheroid structures similar seen animals. Taken together, our data that necessary healthy brain function maintenance opens door therapeutics targeting further exploration neuronal

Language: Английский

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Autophagy-dependent versus autophagy-independent ferroptosis

Trends in Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Ferroptosis is an iron-dependent cell death pathway that, until recently, has been considered to be dependent on autophagy. However, recent studies have reported conflicting results, raising the question about which contexts determine roles of autophagy in ferroptosis. This opinion article addresses this by summarizing and/or diseases a driver or suppressor The execution ferroptosis depends levels (labile) iron, unsaturated (phospho)lipids and free radicals. We propose that context these three factors their upstream pathways are differentially regulated dictates whether positively negatively regulates

Language: Английский

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How does autophagy impact neurological function?

The Neuroscientist, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Autophagies describe a set of processes in which cells degrade their cytoplasmic contents via various routes that terminate with the lysosome. In macroautophagy (the focus this review, henceforth autophagy), contents, including misfolded proteins, protein complexes, dysfunctional organelles, and pathogens, are captured within double membranes called autophagosomes, ultimately fuse lysosomes, after degraded. Autophagy is important maintaining neuronal glial function; consequently, disrupted autophagy associated neurologic diseases. This review provides broad perspective on roles CNS, highlighting recent literature furthers our understanding multifaceted role healthy nervous system.

Language: Английский

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Cadmium-induced iron dysregulation contributes to functional impairment in brain endothelial cells via the ferroptosis pathway

Toxicology and Applied Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 117233 - 117233

Published: Jan. 1, 2025

Language: Английский

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WIPI4 loss linked to ferroptosis

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(4), P. 506 - 507

Published: March 7, 2024

Language: Английский

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A Case of Beta-Propeller Protein-Associated Neurodegeneration With a Unique Truncating Variant in the WDR45 Gene and Uncommon Clinical and Radiologic Findings

Cureus, Journal Year: 2024, Volume and Issue: unknown

Published: April 12, 2024

Beta-propeller protein-associated neurodegeneration (BPAN), a subtype of with brain iron accumulation, is caused by variants in the WDR45 gene. In this paper, we describe patient an atypical presentation BPAN whose whole exome sequencing revealed previously unattested truncating variant gene (c.830+3G>C/p.Leu278Ter), pathogenicity which was verified RNA transcriptomics. A number uncommon neuroanatomic and clinical findings our are discussed, expanding phenotype associated BPAN. This unique case challenges existing genotype-phenotype correlations highlights role X chromosome skewing shaping spectrum

Language: Английский

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Endoplasmic Reticulum-Mitochondria Contacts are apical hotspots of lipid peroxidation driving ferroptosis

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: May 3, 2024

Peroxidation of membrane phospholipids (PLs) is a hallmark ferroptosis. ER and mitochondria have been implicated in ferroptosis, but whether intracellular PL-peroxidation ensues at their contact sites (EMCSs) unknown. Using super-resolution live imaging we charted the immediate spatiotemporal events triggered by ferroptosis inter-organelle level. EMCSs expand minutes after formation localized activated lipid-peroxides that secondary spread to mitochondria, promoting mitochondrial ROS accumulation fission. Oxidative lipidomics unravels host distinct pro-ferroptotic polyunsaturated (PUFA)-PLs, including doubly PUFA-acylated PLs, demonstrating persuasive propensity EMCS PL-peroxidation. Genetic disruption blunts while stabilization enhances them. Analysis human triple-negative breast cancer (TNBC) data shows expression EMCShigh-gene signature associates with ferroptosis-susceptible TNBC subtype harboring heightened levels oxidized-PLs. Our reveal as apical orchestrators lethal lipid-peroxidation production suggest empowering can promote vulnerable cells.

Language: Английский

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The plasma lipids with different fatty acid chains are associated with the risk of hemorrhagic stroke: a Mendelian randomization study

Frontiers in Neurology, Journal Year: 2024, Volume and Issue: 15

Published: July 30, 2024

Background and objective Hemorrhagic stroke, characterized by acute bleeding due to cerebrovascular lesions, is associated with plasma lipids endothelial damage. The causal relationship between genetic lipid levels hemorrhagic stroke remains unclear. This study employs a two-sample Mendelian randomization (MR) analysis explore the profiles different fatty acid chains risk of intracerebral subarachnoid hemorrhage, two main subtypes stroke. Methods datasets for exposure outcome summary statistics were obtained from publicly available sources such as GWAS Catalog, IEU OpenGWAS project, FinnGen. MR was employed initially assess 179 species hemorrhage in Finnish population, leading identification candidate lipids. same methods applied reanalyze data European populations conduct meta-analysis Inverse Variance Weighting (IVW) method served primary inference, additional used complementary analyses. Sensitivity conducted clarify relationships reduce biases. Results Two analyses using performed, followed meta-analyses results. A established 11 specific occurrence within population. Additionally, 5 distinct hemorrhage. Predominantly, linoleic arachidonic side identified. Notably, containing (C20:4) PC 18:1;0_20:4;0 consistently showed decreased both [ p < 0.001; OR(95% CI) = 0.892(0.835–0.954)] 0.002; 0.794(0.689–0.916)]. Conversely, (C18:2) an increased Conclusion identifies potential improving understanding mechanisms behind onset progression

Language: Английский

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Asymmetrical parkinsonism due to novel <i>WDR45</i> variant with beta-propeller protein-associated neurodegeneration (BPAN)

Rinsho Shinkeigaku, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Beta-propeller protein-associated neurodegeneration (BPAN) encompasses a group of refractory neurodegenerative diseases that are caused by excessive iron deposition in the brain, especially basal ganglia. We reported case BPAN with novel variant WDR45 gene at Xp11.23. Our patient was 31-year-old woman who has had an intellectual disability since childhood. Approximately 3 years ago, she developed asymmetric parkinsonism affecting distal right upper and lower limbs. Consistent her neurological findings, dopamine transporter single-photon emission computed tomography demonstrated differences between left sides. She diagnosed as according to genetic analysis, which showed heterozygous (c.345-3C>G) WDR45. To best our knowledge, only few previous reports on have described quantitative neuroimaging parameters These features were similar those Parkinson's disease, among other diseases. report may provide clues elucidate pathological mechanism is disease.

Language: Английский

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