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Pathogenic variants in the WDR45 (OMIM: 300,526) gene on chromosome Xp11 are the genetic cause of a rare neurological disorder characterized by increased iron deposition in the basal ganglia. As WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, the disease has been named Beta-Propeller Protein-Associated Neurodegeneration (BPAN). BPAN represents one of the four most common forms of Neurodegeneration with Brain Iron Accumulation (NBIA). In the current study, we generated and characterized a whole-body Wdr45 knock-out (KO) mouse model. The model, developed using TALENs, presents a 20-bp deletion in exon 2 of Wdr45 . Homozygous females and hemizygous males are viable, proving that systemic depletion of Wdr45 does not impair viability and male fertility in mice. The in-depth phenotypic characterization of the mouse model revealed neuropathology signs at four months of age, neurodegeneration progressing with ageing, hearing and visual impairment, specific haematological alterations, but no brain iron accumulation. Biochemically, Wdr45 KO mice presented with decreased complex I (CI) activity in the brain, suggesting that mitochondrial dysfunction accompanies Wdr45 deficiency. Overall, the systemic Wdr45 KO described here complements the two mouse models previously reported in the literature (PMIDs: 26,000,824, 31,204,559) and represents an additional robust model to investigate the pathophysiology of BPAN and to test therapeutic strategies for the disease.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a relentlessly progressive neurodegenerative disorder caused by mutations in the C19orf12 gene. C19orf12 has been implicated in playing a role in lipid metabolism, mitochondrial function, and autophagy, however, the precise functions remain unknown. To identify new robust cellular targets for small compound treatments, we evaluated reported mitochondrial function alterations, cellular signaling, and autophagy in a large cohort of MPAN patients and control fibroblasts. We found no consistent alteration of mitochondrial functions or cellular signaling messengers in MPAN fibroblasts. In contrast, we found that autophagy initiation is consistently impaired in MPAN fibroblasts and show that C19orf12 expression correlates with the amount of LC3 puncta, an autophagy marker. Finally, we screened 14 different autophagy modulators to test which can restore this autophagy defect. Amongst these compounds, carbamazepine, ABT-737, LY294002, oridonin, and paroxetine could restore LC3 puncta in the MPAN fibroblasts, identifying them as novel potential therapeutic compounds to treat MPAN. In summary, our study confirms a role for C19orf12 in autophagy, proposes LC3 puncta as a functionally robust and consistent readout for testing compounds, and pinpoints potential therapeutic compounds for MPAN.

Background PPCS deficiency disorder (PPCS DD) is an ultra-rare, autosomal recessive form of dilated cardiomyopathy (DCM) caused by pathogenic variants in PPCS, which encodes the enzyme catalyzing the second step in the coenzyme A (CoA) biosynthesis pathway. To date, only six patients worldwide have been identified. Methods Whole-exome sequencing was performed to identify pathogenic PPCS variants in affected individuals. Protein stability was assessed by Western blotting. CoA levels were quantified using a microplate-based assay in patient-derived fibroblasts, cardiac progenitor cells, and cardiomyocytes. Functional evaluation of cardiac cells and engineered heart patches was conducted to investigate contractile performance and arrhythmogenicity. Pantethine was tested as a potential therapeutic agent both in vitro and through long-term clinical follow-up in patients. Results Causative PPCS variants are identified in six individuals with DCM and variable associated features, including neuromuscular and neurological symptoms. Identified variants lead to reduced PPCS protein stability and decreased cellular CoA levels. Cardiac cells exhibit impaired contractility and arrhythmias, which are partially rescued by pantethine treatment. Clinically, patients receiving pantethine show sustained improvement over time. Conclusions Our study expands the genetic and clinical spectrum of PPCS deficiency disorder, identifying six new cases with diverse phenotypes. Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells. Pantethine treatment shows promise in partially rescuing DCM phenotypes, both in vitro and in patients. However, complete reversal may require early intervention. These findings underscore the importance of timely diagnosis and treatment in PPCS DD. Future research should focus on optimizing pantethine supplementation and exploring additional therapies to enhance CoA levels and cardiac function in affected individuals. Zhang, Dorn, Gnutti et al. identify pathogenic PPCS variants in people with PPCS deficiency disorder. Cardiac cells exhibit impaired contractility and arrhythmias, which is partially rescued by pantethine treatment. Plain language summary PPCS deficiency disorder is an extremely rare inherited disease that causes heart muscle weakness (dilated cardiomyopathy) and other symptoms. It results from changes in a gene involved in making coenzyme A (CoA), a vital molecule for cell energy. This study identified six new patients with the condition and investigated how these gene changes affect heart function. Researchers used patient cells and lab-grown heart tissues to study the disease and tested pantethine, a compound that helps increase CoA levels. They found that pantethine improved heart cell function and showed positive effects in treated patients. These results highlight the importance of early diagnosis and treatment. In the future, therapies such as pantethine could offer hope for improving heart health in affected individuals.