Mitochondrial DNA (mtDNA) has received increasing attention in amyotrophic lateral sclerosis (ALS) following the recent report of recurrent low-heteroplasmy mtDNA variants in patients. Here, we performed mtDNA analysis on an independent cohort of 20 sporadic ALS patients using an in-house next-generation sequencing pipeline designed for diagnostics. Using standard filters, none of the previously reported low-heteroplasmy mtDNA variants were detected. These variants only appeared in the low-quality data and were present at similar rates in a large reference population without ALS, localizing to homopolymeric regions that are prone to sequencing errors. Our findings suggest that these low-level mtDNA variants are a result of the technical limitations of short-read next-generation sequencing rather than being associated with the disease.

Glioblastoma (GBM) is the most aggressive primary brain tumor with currently no treatment with long-term efficacy. Systematic relapses and therapeutic resistance are partly associated with the presence of glioblastoma stem cells (GSC) within the tumor. Existing options to overcome GSC protection are limited. Characterizing GSC resistance mechanisms appears crucial to identify efficient targeted inhibitors. A GSC model obtained by dedifferentiation of GBM cell lines (dGSC) was previously validated for GSC characteristics. In this study, viability of dGSC after treatment with diversified cytotoxic drugs was compared to parental cell lines. GSC phenotype acquisition is associated with a greatly decreased sensitivity to most cytotoxic drugs. Proteins expression, cell cycle and iron dosage analyses demonstrated that dGSC resistance acquisition is accompanied by decreased proliferation, STAT3 and Akt activation, increased iron storage and protection against oxidative stress. BMI1 and EZH2 epigenetic regulators are associated with resistance in GBM and were expressed in both dGSC and GBM cells. Akt activation in dGSC could redirect EZH2 toward histone methylation independent functions, through S21 phosphorylation. BMI1 and EZH2 inhibition decreased viability in both GBM cells and dGSC. Notably, EZH2 inhibition through GSK343 decreased proliferation and Akt activation, without impacting EZH2-associated epigenetic modification (H3K27me3), but with the induction of a ferroptosis signature. GSK343 effects on viability, proliferation and ferroptosis were confirmed in two lines of patient-derived GSC. GSK343 overcame resistant dGSC protection to trigger cell death by a mechanism involving oxidative stress. To conclude, GSK343-mediated EZH2 inhibition efficiently eliminated resistant GSC through ferroptosis, in a H3K27me3-independent manner.

INTRODUCTION:Amyotrophic lateral sclerosis (ALS) is a fatal motor neurons disease with multifactorial etiology. The epidemiology of ALS in France is mainly documented through the Limousin regional registry (FRALim). We aimed to determine the incidence and clinical characteristics of ALS cases over a 20-year period in another French region, the Pays de la Loire, served by a single centralized diagnostic center. METHODS:All patients diagnosed with ALS at the Angers University Hospital reference center between 2003 and 2023 were retrospectively included. Demographic and clinical data were extracted from medical records, and incidence rates were calculated using annual population estimates from the National Institute of Statistics and Economic Studies. Spatial analyses were performed to identify over-incidence areas and potential environmental or occupational determinants. RESULTS:A total of 1,316 patients were diagnosed with ALS during the study period, corresponding to a crude incidence rate of 1.88 cases per 100,000 person-years (95% CI: 1.78-1.98), with no significant variation over time. The standardized incidence rate was 1.73 (95% CI: 1.63-1.83). The mean age at symptom onset was 63.6 ± 11.2 years, 58.7% of patients were male. The mean disease duration was 3.7 ± 3.5 years. ALS onset was spinal in 70.3%, bulbar in 27.9%, and respiratory in 1.7% of cases. Familial or genetic forms accounted for 6% of patients. Four geographical over-incidence areas were identified, with no correlation found with pesticide use, air pollution, or other environmental indicators. One occupational cluster was observed among farmers in a specific commune, prompting a dedicated investigation. CONCLUSION:This 20-year retrospective study provides the first epidemiological data on ALS in western France. The incidence and clinical features are consistent with national and European data. The identification of spatial and occupational clusters underlines the importance of continued regional surveillance and of prospective, registry-based studies to clarify environmental and occupational risk factors for ALS.

Neurofilament light chain (NFL) is a structural axonal protein released into extracellular fluids following neuroaxonal injury. Blood-based NfL measurement has emerged as a marker of neurodegeneration, but its relevance in geriatric psychiatry remains insufficiently defined. We conducted a narrative review of peer-reviewed studies reporting serum or plasma NfL concentrations in older adults with neurodegenerative diseases or major psychiatric disorders. In MEDLINE/PubMed, were searched up to 31 October 2025. We synthesised data on normative values and biological determinants, compared NfL levels across diagnostic categories, examined evidence from mild behavioral impairment and late-onset psychiatric presentations, and developed a clinically oriented interpretative framework. Across studies, blood NfL concentrations increased with age and were influenced by medical comorbidities, particularly renal function. Neurodegenerative disorders were associated with higher NfL levels than primary psychiatric disorders, whereas most psychiatric conditions overlapped with age-adjusted normative ranges. Meta-analytic evidence showed no significant elevation in major depressive disorder and modest, heterogeneous increases in bipolar disorder, while schizophrenia spectrum disorders largely overlapped with physiological ageing. In transdiagnostic contexts, including mild behavioral impairment and late-onset psychiatric syndromes, higher baseline NfL levels and steeper longitudinal increases were associated with greater risk of underlying neurodegeneration. These findings support a stepwise interpretation strategy integrating age, comorbidities, clinical context and longitudinal trajectories. Age- and comorbidity-adjusted interpretation of blood NfL can support risk stratification in geriatric psychiatry. Used as an adjunctive biomarker, NfL may help identify patients requiring monitoring or additional neurological assessment.

Objectives The identification of bi-allelic intermediate ATXN2 repeat expansions in a pedigree with amyotrophic lateral sclerosis (ALS) through clinical testing prompted us to investigate its relevance in the wider ALS population.Methods ATXN2 repeat size was assessed in a large international cohort of ALS patients (n=6653 from Project MinE) and in neurologically intact control populations (n=13 515 controls from Project MinE and gnomad). For bi-allelic cases, we retrieved medical records, family history and MRI imaging. For familial cases, we obtained DNA samples from relatives for segregation analyses.Results In total, we identified bi-allelic intermediate ATXN2 repeat expansions in five familial cases from three different pedigrees and five apparently sporadic cases. There is a relatively homogeneous phenotype characterised by lower limb onset and long survival (median 6 years) without significant cerebellar atrophy. Bi-allelic expansions were absent in controls (0 out of 13 515).Discussion Here we report an apparently novel autosomal recessive form of familial ALS caused by bi-allelic intermediate ATXN2 repeat expansions, which is characterised by high penetrance, lower limb onset and slow progression. Although rare, testing for ATXN2 expansions should be performed in the clinical setting given its relevance to prognosis and genetic counselling.

Hereditary optic neuropathies, including dominant optic atrophy and Leber's hereditary optic neuropathy, are genetic disorders characterized by retinal ganglion cell degeneration leading to vision loss, mainly associated with mitochondrial dysfunction. In this study, we analysed mitochondrial distribution and ultrastructure in the retina and longitudinal optic nerve sections of pre-symptomatic hereditary optic neuropathies mouse models with Opa1 and Nd6 deficiency to identify early mitochondrial changes. Our results show significant mitochondrial fragmentation and increased mitophagy in Opa1+/- mice, indicating early mitochondrial changes prior to neuronal loss. Conversely, Nd6P25L mice exhibited mitochondrial hypertrophy, suggesting an adaptive response to compensate for altered energy metabolism. These pre-symptomatic mitochondrial changes were mainly observed in the unmyelinated portion of the retinal ganglion cell axons, where the transmission of the visual information requires high energy expenditure, constituting the specific point of vulnerability in hereditary optic neuropathies. These findings highlight early focal mitochondrial changes prior to neuronal loss in hereditary optic neuropathies and provide insight into pre-symptomatic therapeutic approaches. Bureau et al. report that early mitochondrial changes, including fragmentation and increased mitophagy in Opa1+/- mice and mitochondrial hypertrophy in Nd6P25L mice, occur before neuronal loss in hereditary optic neuropathies. These changes are predominantly observed in the unmyelinated portion of retinal ganglion cell axons, suggesting potential early therapeutic targets.

Mitochondrial dynamics is a process that balances fusion and fission events, the latter providing a mechanism for segregating dysfunctional mitochondria. Fission is controlled by the mitochondrial membrane potential (ΔΨm), optic atrophy 1 (OPA1) cleavage, and DRP1 recruitment. It is thought that this process is closely linked to the activity of the mitochondrial respiratory chain (MRC). However, we report here that MRC inhibition does not decrease ΔΨm nor increase fission, as evidenced by hyperconnected mitochondria. Conversely, blocking F0F1-ATP synthase activity induces fragmentation. We show that the F0F1-ATP synthase is sensing the inhibition of MRC activity by immediately promoting its reverse mode of action to hydrolyze matrix ATP and restoring ΔΨm, thus preventing fission. While this reverse mode is expected to be inhibited by the ATPase inhibitor ATPIF1, we show that this sensing is independent of this factor. We have unraveled an unexpected role of F0F1-ATP synthase in controlling the induction of fission by sensing and maintaining ΔΨm.

The identification of biomarkers for amyotrophic lateral sclerosis (ALS) is a central issue in disease research. In a recent article, Chatterjee et al. show that blood extracellular vesicles (EVs) with high levels of transactive response DNA-binding protein 43 (TDP-43) accurately discriminate patients with ALS from controls and correlate with disease severity, providing a promising biomarker for early diagnosis and monitoring.

Il termine “encefalopatia” designa una sofferenza cerebrale diffusa a esordio acuto o subacuto, che altera lo stato mentale e/o il livello di vigilanza del paziente. I disturbi neurocomportamentali sono il più delle volte in primo piano; in uno stadio più avanzato possono svilupparsi disturbi della vigilanza, la cui gravità può variare dalla sonnolenza al coma. Le encefalopatie metaboliche e tossiche possono essere secondarie alla carenza o all’accumulo di una sostanza endogena o alla presenza di una sostanza esogena tossica. Alcuni elementi sono suggestivi, come la presenza di asterixis e di miocloni o l’esistenza di onde trifasiche all’elettroencefalogramma. La diagnosi eziologica può essere immediatamente orientata dal terreno del paziente, dal contesto di insorgenza o anche dall’esistenza di specifici punti di allerta clinici o paraclinici. In assenza di indicazioni, è necessario ipotizzare uno per uno i gruppi eziologici che possono essere all’origine di un’encefalopatia metabolica o tossica affrontati in questo articolo. In tutti i casi, il miglioramento clinico dopo l’implementazione del trattamento è un elemento centrale nella riflessione diagnostica.

The diagnosis of amyotrophic lateral sclerosis (ALS) is based on evidence of upper and lower motor neuron degeneration in the bulbar, cervical, thoracic, and lumbar regions in a patient with progressive motor weakness, in the absence of differential diagnosis. Despite these well-defined criteria, ALS can be difficult to diagnose, given the wide variety of clinical phenotypes. Indeed, the central or peripheral location of the disease varies with a spectrum ranging from predominantly central to exclusively peripheral, symptoms can be extensive or limited to the limbs, bulbar area or respiratory muscles, and the duration of the disease may range from a few months to several decades. In the absence of a specific test, the diagnostic strategy relies on clinical, electrophysiological, biological and radiological investigations to confirm the disease and exclude ALS mimics. The main challenge is to establish a diagnosis based on robust clinical and paraclinical evidence without delaying treatment initiation by increasing the number of additional tests. This approach requires a thorough knowledge of the phenotypes of ALS and its main differential diagnoses.

Introduction Une des énigmes des neuropathies optiques héréditaires liées aux mutations portant sur des protéines mitochondriales réside dans la spécificité de l’atteinte du nerf optique. L’une des clefs pourrait se situer au niveau de la lame criblée du nerf optique, où débute sa myélinisation. Objectifs Rechercher des différences dans l’ultrastructure mitochondriale au niveau de la lame criblée du nerf optique de souris transgéniques porteuses de mutations sur les gènes OPA1 et ND6. Méthodes Nous avons comparé l’ultrastructure mitochondriale en immunofluorescence et microscopie électronique chez 3 groupes de modèles murins âgés de 5 mois, pré-symptomatiques : un groupe porteur de la mutation nucléaire OPA1± (atrophie optique dominante), un groupe porteur de la mutation mitochondriale ND6 (neuropathie optique de Leber), et un groupe contrôle sain (WT). Résultats Dans les 3 groupes, nous retrouvions des mitochondries de structure différente de part et d’autre de la lame criblée : plus nombreuses, plus rondes et de contenu matriciel plus clair dans la zone non myélinisée du nerf optique. La densité mitochondriale était plus importante dans le groupe OPA1± avec des amas de mitochondries plus petites et altérées. La surface mitochondriale était à l’inverse augmentée dans le groupe ND6 (Fig. 1). Discussion Les nombreuses mitochondries avec une structure différente répondent à la demande énergétique majeure dans la zone non myélinisée du nerf optique. Les anomalies chez les souris OPA1± traduisent un défaut précoce de fusion mitochondriale. La surface mitochondriale augmentée dans le groupe ND6 peut traduire une compensation quantitative de la chaîne respiratoire défectueuse. Conclusion Il existe des altérations mitochondriales pré-symptomatiques distinctes au niveau du nerf optique des modèles de neuropathies optiques génétiques, fournissant des critères de réponse aux thérapies géniques.

Background: The architecture and composition of glial (GCI) and neuronal (NCI) alpha-synuclein inclusions observed in multiple system atrophy (MSA) remain to be precisely defined to better understand the disease. Methods: Here, we used stochastic optical reconstruction microscopy (STORM) to characterize the nanoscale organization of glial (GCI) and neuronal (NCI) alpha-synuclein inclusions in cryopreserved brain sections from MSA patients. Results: STORM revealed a dense cross-linked internal structure of alpha-synuclein in all GCI and NCI. The internal architecture of hyperphosphorylated alpha-synuclein (p-alpha Syn) inclusions was similar in glial and neuronal cells, suggesting a common aggregation mechanism. A similar sequence of p-alpha Syn stepwise intracellular aggregation was defined in oligodendrocytes and neurons, starting from the perinuclear area and growing inside the cells. Consistent with this hypothesis, we found a higher mitochondrial density in GCI and NCI compared to oligodendrocytes and neurons from unaffected donors (P < 0.01), suggesting an active recruitment of the organelles during the aggregation process. Conclusions: These first STORM images of GCI and NCI suggest stepwise alpha-synuclein aggregation in MSA. (c) 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

AbstractThe centrosome, as the main microtubule organizing centre, plays key roles in cell polarity, genome stability and ciliogenesis. The recent identification of ribosomes, RNA-binding proteins and transcripts at the centrosome suggests local protein synthesis. In this context, we hypothesized that TDP-43, a highly conserved RNA binding protein involved in the pathophysiology of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, could be enriched at this organelle. Using dedicated high magnification sub-diffraction microscopy on human cells, we discovered a novel localization of TDP-43 at the centrosome during all phases of the cell cycle.These results were confirmed on purified centrosomes by western blot and immunofluorescence microscopy. In addition, the co-localization of TDP-43 and pericentrin suggested a pericentriolar enrichment of the protein, leading us to hypothesize that TDP-43 might interact with local mRNAs and proteins. Supporting this hypothesis, we found four conserved centrosomal mRNAs and 16 centrosomal proteins identified as direct TDP-43 interactors. More strikingly, all the 16 proteins are implicated in the pathophysiology of TDP-43 proteinopathies, suggesting that TDP-43 dysfunction in this organelle contributes to neurodegeneration.This first description of TDP-43 centrosomal enrichment paves the way for a more comprehensive understanding of TDP-43 physiology and pathology.

The diagnosis of neurodegenerative diseases is made complex by the heterogenous phenotype of the patients and the regular occurrence of concomitant pathology. Studying clinicopathological correlations in autopsy series is a central approach to improve pathological prediction in clinical practice. However, such method requires a wealth of information, and the use of standard spreadsheet software is hardly suitable. To overcome this constraint, we designed a customizable and freely available neuropathology form with 456 data entry fields driven by an open-source DataBase Management Systems (DBMS) using Structured Query Language (SQL). This approach allowed us to optimize the compilation of clinical and pathological data from our brain collection (264 autopsied patients, 22,885 data points). Information was then easily retrieved using general and specific queries, facilitating the analysis of demographics, clinicopathological correlations, and incidental and concomitant proteinopathies. Tau, amyloid-β and α-synuclein incidental pathology was observed in respectively 78.1%, 42.8%, and 10.7% of all the patients. These proportions increased with age, reaching 100% for Tau pathology after 80. Concomitant proteinopathy was observed in 46.4% of the patients diagnosed with neurodegenerative diseases and prion disease. We observed a particularly high rate of co-pathology in patients with Dementia with Lewy bodies (81.3% of associated Tau and amyloid-β pathology) and Creutzfeldt-Jakob disease (68.4% of associated Tau pathology). Finally, we used specific queries to identify old cases that could meet newly defined neuropathological criteria and revised the diagnosis of a 90-year-old patient to LATE Stage 2. Increasing our understanding of clinicopathological correlations in neurodegenerative diseases is crucial given the implications in clinical diagnosis, biomarker identification and targeted therapies assessment. The precise characterization of clinical and pathological data of autopsy series remains a central approach but the large amount of generated data should encourage a more systematic use of DBMS.

Le diagnostic de Sclérose latérale amyotrophique (SLA) repose sur l’association de signes de souffrance des neurones moteurs centraux et périphériques d’extension progressive au niveau des sphères bulbaire, cervicale, thoracique et lombaire, en l’absence de diagnostic différentiel permettant d’expliquer les symptômes. Le bilan organisé chez un patient présentant des signes évocateurs de la maladie doit donc être clinique, électrophysiologique, biologique et radiologique. L’objectif de ce bilan est d’étayer le diagnostic de SLA et d’écarter les pathologies – en particulier curables – pouvant mimer la maladie. Cette approche implique une bonne connaissance des différents phénotypes cliniques de la SLA et de ses principaux diagnostics différentiels.

L'étude des corrélations clinico-pathologiques reste centrale pour améliorer la prédiction diagnostique dans les maladies neurodégénératives. Le volume d'informations nécessaires pour cette approche rend difficile l'utilisation de tableurs usuels. Utiliser un logiciel de base de données informatisé pour étudier les corrélations clinico-pathologiques chez les patients atteints de maladies neurodégénératives autopsiés au CHU d'Angers entre 2005 et 2020. Un formulaire de saisie de données standardisé, anonymisé et personnalisable a été élaboré à l'aide d'un système de gestion de base de données (SGBD) open-source, avec 456 champs de saisie possibles par patient. Une base de données relationnelle a été créée à partir de ce formulaire pour recueillir et analyser les données cliniques et histologiques des 264 patients autopsiés dans le département de Neuropathologie du CHU d'Angers entre 2005 et 2020 (Fig. 1). Cette approche a permis d'optimiser le recueil et l'analyse des données cliniques et histologiques de notre biocollection (22 885 points de données). Nous avons pu facilement récupérer les informations en utilisant des requêtes générales et spécifiques pour étudier les données démographiques, les corrélations clinico-pathologiques et le concept de co-pathologies. Nous avons également pu redresser le diagnostic de cas suivant la parution de nouvelles classifications et entités en neuropathologie. (Fig. 2, Fig. 3, Fig. 4, Tableaux 1–3, Tableau 4, Tableau 5). Grâce à l'utilisation de SGBD dédiés utilisant un langage de requête structuré (SQL), nous avons pu facilement réaliser des analyses corrélatives en neuropathologie basées sur un important volume de données. Améliorer notre compréhension des corrélations clinico-pathologiques est crucial compte tenu des implications dans le diagnostic clinique, l'identification de biomarqueurs et les essais cliniques de thérapies ciblées. La grande quantité de données générées inhérente aux approches corrélatives et les possibilités grandissantes d'utiliser des algorithmes d'intelligence artificielle devraient encourager l'emploi plus systématique des SGBD en neuropathologie.

Amyotrophic lateral sclerosis (ALS) is a rare fatal motor neuron disease. Although many potential mechanisms have been proposed, the pathophysiology of the disease remains unknown. Currently available treatments can only delay the progression of the disease and prolong life expectancy by a few months. There is still no definitive cure for ALS, and the development of new treatments is limited by a lack of understanding of the underlying biological processes that trigger and promote neurodegeneration. Several scientific results suggest a neurovascular impairment in ALS providing perspectives for the development of new biomarkers and treatments. In this article, we performed a systematic review using PRISMA guidelines including PubMed, EmBase, GoogleScholar, and Web of Science Core Collection to analyze the scientific literature published between 2000 and 2021 discussing the neurocardiovascular involvement and ophthalmologic abnormalities in ALS. In total, 122 articles were included to establish this systematic review. Indeed, microvascular pathology seems to be involved in ALS, affecting all the neurovascular unit components. Retinal changes have also been recently highlighted without significant alteration of the visual pathways. Despite the peripheral location of the retina, it is considered as an extension of the central nervous system (CNS) as it displays similarities to the brain, the inner blood–retinal barrier, and the blood–brain barrier. This suggests that the eye could be considered as a 'window' into the brain in many CNS disorders. Thus, studying ocular manifestations of brain pathologies seems very promising in understanding neurodegenerative disorders, mainly ALS. Optical coherence tomography angiography (OCT-A) could therefore be a powerful approach for exploration of retinal microvascularization allowing to obtain new diagnostic and prognostic biomarkers of ALS.

Glioblastoma is an aggressive brain tumor with a poor prognosis. Glioblastoma Stem Cells (GSC) are involved in glioblastoma resistance and relapse. Effective glioblastoma treatment must include GSC targeting strategy. Robust and well defined in vitroGSC models are required for new therapies evaluation. In this study, we extensively characterized 4 GSC models obtained by dedifferentiation of commercially available glioblastoma cell lines and compared them to 2 established patient derived GSC lines (Brain Tumor Initiating Cells). Dedifferentiated cells formed gliospheres, typical for GSC, with self-renewal ability. Gene expression and protein analysis revealed an increased expression of several stemness associated markers such as A2B5, integrin α6, Nestin, SOX2 and NANOG. Cells were oriented toward a mesenchymal GSC phenotype as shown by elevated levels of mesenchymal and EMT related markers (CD44, FN1, integrin α5). Dedifferentiated GSC were similar to BTIC in terms of size and heterogeneity. The characterization study also revealed that CXCR4 pathway was activated by dedifferentiation, emphasizing its role as a potential therapeutic target. The expression of resistance-associated markers and the phenotypic diversity of the 4 GSC models obtained by dedifferentiation make them relevant to challenge future GSC targeting therapies.