ATP-binding cassette transporter subfamily B member 7 (ABCB7) is a mitochondrial ATP-driven pump essential for cytosolic iron-sulfur (Fe-S) cluster biogenesis and cellular iron homeostasis. Mutations in ABCB7 are linked to X-linked sideroblastic anemia with ataxia (XLSA/A). Here, we demonstrate that the ATPase activity of ABCB7 is stimulated by iron and cobalt protoporphyrin IX (hemin and CoPP) in the presence of glutathione (GSH), highlighting an additional role for ABCB7 as a metalloporphyrin exporter. Using single-particle cryo-electron microscopy, we determine the structures of human ABCB7 in multiple functional states at resolutions of up to 2.3 Å. Our structures reveal a putative substrate-binding cavity that accommodates two stacked CoPP molecules conjugated by two GSH cysteine thiols. The conserved residue F426 controls substrate entrapment and release as a molecular gate. We further show that at high substrate concentrations excess CoPP easily partitions into the lipid bilayer, where the hydrophobic environment stabilizes the porphyrin macrocycle and limits the aggregation or redox reactivity that is prone to occur with free porphyrins in aqueous solution. Finally, our structure analyses rationalize the pathogenic effect of the E433K mutation associated with XLSA/A disease.

Anticholinergic pharmacological agents are commonly misused because of their euphoric effects, increased energy, improved mood, and enhanced social interactions. Some herbal products with anticholinergic properties can also be abused for their psychoactive effects. One such ornamental plant is Brugmansia suaveolens, which contains alkaloids including atropine and scopolamine and can produce toxic effects. This case report describes a male patient with Brugmansia suaveolens abuse and coexisting multiple substance use disorders. The patient reported consuming a decoction of Brugmansia suaveolens leaves and flowers as a daily tea for four years to obtain relief. He experienced anticholinergic symptoms, including drowsiness, sedation, agitation, ataxia, dry mouth, palpitations, fever, and visual and auditory hallucinations while under the influence of the plant. The patient was discharged following a four-week treatment course. Plants like Brugmansia suaveolens, which have anticholinergic but toxic properties, may be misused, especially by individuals with a history of multiple substance use disorders.

Pathogenic MSTO1 mutations cause cerebellar ataxia and congenital myopathy, yet their molecular mechanisms remain poorly understood. This study identifies MSTO1 as a crucial regulator of mitochondrial genome integrity through direct interaction with RAD51. MSTO1 deficiency enhances RAD51 binding to mitochondrial DNA (mtDNA), disrupting mtDNA replication and causing mtDNA damage. This interaction, mediated by the conserved FxxA motif, specifically regulates RAD51's mitochondrial activity without affecting its nuclear roles. Loss of MSTO1 impairs mitochondrial membrane potential, reduces mtDNA content, and increases susceptibility to oxidative stress. Furthermore, MSTO1 deficiency triggers BAX/BAK-dependent mtDNA leakage, activating the cGAS-STING pathway and driving inflammatory responses. Clinical bioinformatics further link low MSTO1 expression with immune activation in cancers. Our findings establish MSTO1 as a modulator of RAD51 activity within mitochondria, regulating mitochondrial stability and immune responses. This provides insights into MSTO1-related diseases and suggests MSTO1 as a potential target for activating anti-tumor immune responses in cancer cells.

The human cerebellum is implicated in various neurological and psychiatric diseases, but its complex development and cellular diversity have posed challenges for in vitro modeling. Here, we report the generation of human induced pluripotent stem cell (iPSC)-derived cerebellar organoids (hCBOs) that are characterized by induction of rhombomere 1 (R1) cellular identity and followed by derivation of typical neuronal and glial cell types of the cerebellum. In contrast to forebrain organoids with multiple neural rosettes and inside-out neuronal migration, hCBOs develop a germinal zone on the outermost surface of the organoids with outside-in neuronal migration. These hCBOs produce various neuronal cell types resembling granule neurons, Purkinje cells, Golgi neurons, and deep cerebellar nuclei. By using a glial induction strategy, we generate Bergmann glial cells (BGCs) that serve as scaffolds for migratory granule cells and enhance electrophysiological activity of the hCBOs. Furthermore, by generating hCBOs from patients with Friedreich's ataxia (FRDA), we reveal disease-specific phenotypes that can be reversed by histone deacetylase (HDAC) inhibitors and gene editing by CRISPR-Cas9. Taken together, our advanced hCBO model provides new opportunities to investigate the mechanisms of cerebellar ontogenesis and utilize patient-derived iPSCs for translational research.

Biallelic pathogenic variants of the Reticulon 4 interacting protein 1 (RTN4IP1) gene are responsible for optic atrophy, either isolated or associated with ataxia, mental retardation, and seizures. They are identified as a cause of hereditary optic neuropathy in 7% of patients diagnosed before the age of 20. We have built a dataset for this gene by collating all the clinical cases available in the literature, and unpublished patients diagnosed at our centre, using standard nomenclature to describe both the molecular and phenotypic features. We performed a comprehensive data analysis, based on computational reasoning, to provide an overall picture of the dataset and validate its relevance. This new dataset provides an updated genetic map of the reported pathogenic variants, an ontological annotation of phenotypic abnormalities in a grid format showing clinical heterogeneity, and a full interoperability with the databases of other genetic forms of optic neuropathies.

Over the past century, research on vitamin E has evolved from its initial identification as a fertility factor to the recognition of α-tocopherol (α-TOH) as an essential micronutrient with antioxidant and gene regulatory functions. Despite extensive investigation, controversies persist regarding its precise biological role, clinical efficacy, and classification as a vitamin. This review summarizes scientific milestones in vitamin E (tocochromanol) research. It highlights recent advances in understanding the absorption, metabolism, and molecular mechanisms of vitamin E. The review also outlines unresolved questions and methodological challenges. The focus is on α-TOH and its metabolites, which exhibit biological activities beyond classical antioxidant effects, such as the regulation of inflammation, lipid metabolism, and immune responses. Evidence from genetic, biochemical, and clinical studies supports the essentiality of α-TOH in humans, as demonstrated by ataxia with vitamin E deficiency (AVED). Other tocochromanols and their metabolites exhibit promising biological activities that suggest potential therapeutic applications. However, their physiological relevance must be confirmed. Advances in metabolomic profiling and molecular modeling now allow for a more comprehensive characterization of vitamin E metabolism and function. Understanding the molecular pathways and biological roles of vitamin E and its derivatives is crucial for refining its definition, establishing evidence-based dietary recommendations, and evaluating its potential in disease prevention and therapy.

Spinocerebellar ataxia type 27B (SCA27B), caused by an intronic GAA repeat expansion in the FGF14 gene, has recently emerged as a major cause of late-onset cerebellar ataxia (LOCA). Its prevalence and clinical profile in Central and Eastern Europe remain largely unknown. To determine the frequency and phenotypic characteristics of FGF14 GAA·TTC repeat expansions, a large cohort of Polish patients with undiagnosed adult-onset cerebellar ataxia was investigated. We retrospectively analyzed 701 patients (age of onset ≥ 25 years) with adult-onset cerebellar ataxia of unknown etiology, previously tested negative for SCA1, SCA2, SCA3, SCA8, and RFC1 expansions. GAA·TTC repeat lengths were assessed using long-range and repeat-primed PCR. Expansions ≥ 250 repeats were classified as pathogenic. Clinical and MRI data were evaluated where available. A control group of 66 neurologically healthy individuals was also screened. Pathogenic FGF14 expansions (≥ 250 repeats) were identified in 4.4% (31/701) of patients, including 23 with fully penetrant (≥ 300) and 8 with incompletely penetrant (250-299) alleles. No pathogenic expansions were found in controls. The mean age of onset was 49.8 years. Common symptoms included balance and gait disturbances, cerebellar syndrome, and episodic features such as diplopia. Cerebellar atrophy was present in 45% of patients with available MRI. No significant correlation between repeat length and age of onset was observed. Our findings confirm that FGF14 repeat expansions are an underrecognized cause of LOCA in Poland and support their inclusion in standard genetic testing for adult-onset ataxias. Further studies are warranted to better define penetrance and genotype-phenotype correlations.

Multiple system atrophy (MSA) is a neurodegenerative condition causing parkinsonism, cerebellar ataxia and/or dysautonomia. Typical survival is between 6-10 years, but some people die before five or after 15 years. This heterogeneity complicates advanced planning and clinical trial stratification. MSA prognostication studies have shown conflicting results, possibly due to diagnostic accuracy or study size. We report results from a study of survival prognostic factors in a cohort of 555 MSA patients (including the largest post-mortem confirmed cohort to date of 254 people) gathered through the Queen Square Brain Bank and the PROSPECT-M-UK multi-centre prospective cohort study. Through PROSPECT-M-UK, 318 clinically diagnosed MSA patients (17 overlapped with the QSBB cohort) were followed up annually over 5 years. The QSBB cohort clinical data was collected through retrospective review of primary and secondary care documentation. Survival analysis was performed using counting process Cox proportionate hazards modelling, Kaplan-Meier log-rank testing and landmark survival analysis to account for guarantee-time bias. Mean onset age in the combined cohort was 58.7±9.0y with median survival of 8.25y (95% CI:7.88-8.63). 28.8% were clinically diagnosed in-life with MSA-P, 23.8% MSA-C, 40.2% mixed and the rest as non-MSA diagnoses. Later disease onset was associated with shorter survival (HR=1.04, P<0.001). The commonest cause of death was respiratory infection (67%) followed by disease related decline (20%). Median survival from indoor wheelchair use, gastrostomy insertion or development of unintelligible speech was consistently <1.5 years (95% CI upper limits<2.4 years), making these reliable late-stage disease markers. Using landmark analysis, at 3 years from onset, negative prognostic factors included recurrent falls, unintelligible speech, use of catheters and of medication for orthostatic hypotension (HR = 1.57, 3.29, 1.76, 3.29;all P<0.05). At 5 years from onset, mobility milestones including walking aid use, outdoor and indoor wheelchair use (HR = 1.70, 1.93, 2.62;all P<0.01) became significant, whilst dysautonomia milestones (catheter and orthostatic support medication use) were no longer significant. Median individual Unified Multiple System Atrophy Rating Scale (UMSARS) progression rate (n=91) was 10.27 (IQR:5.31-14.30) points/year and did not correlate with symptom duration. Higher baseline UMSARS and faster UMSARS progression were negative prognostic factors of survival from baseline review (HR=1.03 and 1.07 respectively, both P<0.001). We show that in-clinic rating scales and clinical milestone assessment can aid MSA prognostication. Importantly, prognostic factors demonstrate time-dependent variability, which may contribute to previous heterogeneity observed in smaller studies. This knowledge is important for patient care and should inform future clinical trial stratification.

Ataxia-telangiectasia and Rad3-related (ATR) is an essential DNA damage response kinase that protects genome integrity by controlling cell cycle checkpoints, regulating origin firing, stabilizing replication forks, and signaling DNA repair. Due to hyper-proliferation, cancer cells depend on ATR for survival, implicating ATR inhibitors as promising therapeutics. However, variable tumor responses to ATR inhibitors highlights the need to uncover the determinants of cell fate. Here, we show breast cancer sensitivity to ATR inhibition correlates with the appearance of pan-nuclear DNA damage. The fate of these cells is driven by a p53-p21-RB1 axis that triggers a G2-to-G0-like cell cycle exit and is buffered by the p53 inhibitor MDM2. MDM2 inhibition lowers the DNA damage threshold for cell cycle exit and robustly targets ATR inhibitor-resistant cells. Our work reveals cell cycle plasticity as a mechanism determining cell fate during ATR inhibition and identifies MDM2 as a target for increasing ATR inhibitor efficacy.