Age-related Purkinje cell death is steroid dependent: RORα haplo-insufficiency impairs plasma and cerebellar steroids and Purkinje cell survival

A major problem of ageing is progressive impairment of neuronal function and ultimately cell death. Since sex steroids are neuroprotective, their decrease with age may underlie age-related neuronal degeneration. To test this, we examined Purkinje cell numbers, plasma sex steroids and cerebellar neurosteroid concentrations during normal ageing (wild-type mice, WT), in our model of precocious ageing (Rora+/sg, heterozygous staggerer mice in which expression of the neuroprotective factor RORα is disrupted) and after long-term hormone insufficiency (WT post-gonadectomy). During normal ageing (WT), circulating sex steroids declined prior to or in parallel with Purkinje cell loss, which began at 18 months of age. Although Purkinje cell death was advanced in WT long-term steroid deficiency, this premature neuronal loss did not begin until 9 months, indicating that vulnerability to sex steroid deficiency is a phenomenon of ageing Purkinje neurons. In precocious ageing (Rora+/sg), circulating sex steroids decreased prematurely, in conjunction with marked Purkinje cell death from 9 months. Although Rora+/sg Purkinje cells are vulnerable through their RORα haplo-insufficiency, it is only as they age (after 9 months) that sex steroid failure becomes critical. Finally, cerebellar neurosteroids did not decrease with age in either genotype or gender; but were profoundly reduced by 3 months in male Rora+/sg cerebella, which may contribute to the fragility of their Purkinje neurons. These data suggest that ageing Purkinje cells are maintained by circulating sex steroids, rather than local neurosteroids, and that in Rora+/sg their age-related death is advanced by premature sex steroid loss induced by RORα haplo-insufficiency

The role of sex steroid hormones in Purkinje cell death in the staggerer mutant during aging and development

The comprehension of neuronal degeneration during aging has become one of the major objectives in Neuroscience during the last decades. This thesis will focus on both endocrine and neural senescence since they overlap during the aging process and are mechanistically intertwined. This thesis is divided into two main themes involving the staggerer mutant (Rorα sg/sg), a natural mutant of RORα (Retinoid acid receptor-related Orphan Receptor α) nuclear recemptor: I) the relationship, in vivo, between (neuro)endocrine aging, degenerative disorders and genetic make-up in the cerebellum II) characteristics of the development of the Rorα sg/sg cerebellum and of its synaptic architecture ex vivo.

The role of sex steroid hormones in Purkinje cell death in the staggerer mutant during development and aging

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Formation and Maturation of Parallel Fiber-Purkinje Cell Synapses in the Staggerer Cerebellum Ex Vivo

In vivo, homozygous staggerer (Rora(sg/sg)) Purkinje cells (PCs) remain in an early stage of development with rudimentary spineless dendrites, associated with a lack of parallel fiber (PF) input and the persistence of multiple climbing fibers (CFs). In this immunocytochemical study we used cerebellar organotypic cultures to monitor the development of Rora(sg/sg) PF-PC synapses in the absence of CF innervation. Ex vivo the vesicular glutamate transporters VGluT1 and VGluT2 reactivity was preferentially localized around the Rora(sg/sg) PC soma and proximal dendrites, which are typically CF domains. The shift from VGluT2 to VGluT1 in PF terminals during development was delayed in Rora(sg/sg) slices. The postsynaptic receptors mGluR1 and GluR52 were differently distributed on Rorasglsg PCs. mGluR1 reactivity was evenly distributed in PC soma and dendrites, whereas GluRS2 reactivity, normally restricted at PF synapses, was dense in Rora(sg/sg) PC somata. The presynaptic distribution of VGluT1 and VGluT2 on Rora'glsg PCs matched the postsynaptic distribution of the glutamate receptor GluR82, but not mGluR1. J. Comp. Neurol. 512: 467-477,2009. (c) 2008 Wiley-Liss, Inc

Lipodystrophic syndromes: From diagnosis to treatment

International audienceLipodystrophic syndromes are acquired or genetic rare diseases, characterised by a generalised or partial lack of adipose tissue leading to metabolic alterations linked to strong insulin resistance. They encompass a variety of clinical entities due to primary defects in adipose differentiation, in the structure and/or regulation of the adipocyte lipid droplet, or due to immune-inflammatory aggressions, chromatin deregulations and/or mitochondrial dysfunctions affecting adipose tissue. Diagnosis is based on clinical examination, pathological context and comorbidities, and on results of metabolic investigations and genetic analyses, which together determine management and genetic counselling. Early lifestyle and dietary measures focusing on regular physical activity and avoiding excess energy intake are crucial. They are accompanied by multidisciplinary follow-up adapted to each clinical form. In case of hyperglycemia, antidiabetic medications, with metformin as a first-line therapy in adults, are used in addition to lifestyle and dietary modifications. When standard treatments have failed to control metabolic disorders, the orphan drug metreleptin, an analog of leptin, can be effective in certain forms of lipodystrophy syndrome. Metreleptin therapy indications, prescription and monitoring were recently defined in France, representing a major improvement in patient care

Diagnostic et parcours de soin chez les patients avec lipodystrophies et syndromes rares d'insulino-résistance: point d'étape à partir d'un centre de référence National

International audienceBACKGROUND:Rare syndromes of lipodystrophy and insulin-resistance display heterogeneous clinical expressions. Their early recognition, diagnosis and management are required to avoid long-term complications. OBJECTIVE:We aimed to evaluate the patients’ age at referral to our dedicated national reference center in France and their elapsed time from first symptoms to diagnosis and access to specialized care. PATIENTS AND METHODS:We analyzed data from patients with rare lipodystrophy and insulin-resistance syndromes referred to the coordinating PRISIS reference center (Adult Endocrine Department, Saint-Antoine Hospital, AP-HP, Paris), prospectively recorded between 2018 and 2023 in the French National Rare Disease Database (BNDMR, Banque Nationale de Données Maladies Rares ). RESULTS:A cohort of 292 patients was analyzed, including 208 women, with the following diagnosis: Familial Partial LipoDystrophy (FPLD, n = 124, including n = 67 FPLD2/Dunnigan Syndrome); Acquired lipodystrophy syndromes ( n = 98, with n = 13 Acquired Generalized Lipodystrophy, AGL); Symmetric cervical adenolipomatosis (n = 27, Launois-Bensaude syndrome, LB), Congenital generalized lipodystrophy (n = 18, CGL) and other rare severe insulin-resistance syndromes (n = 25). The median age at referral was 47.6 years [IQR: 31–60], ranging from 25.2 (CGL) to 62.2 years old (LB). The median age at first symptoms of 27.6 years old [IQR: 16.8–42.0]) and the median diagnostic delay of 6.4 years [IQR: 1.3–19.5] varied among diagnostic groups. The gender-specific expression of lipodystrophy is well-illustrated in the FPLD2 group (91% of women), presenting with first signs at 19.3 years [IQR: 14.4–27.8] with a diagnostic delay of 10.5 years [IQR: 1.8–27.0].CONCLUSION:The national rare disease database provides an important tool for assessment of care pathways in patients with lipodystrophy and rare insulin-resistance syndromes in France. Improving knowledge to reduce diagnostic delay is an important objective of the PRISIS reference center.CONTEXTE :Les syndromes rares de lipodystrophies et de résistance à l'insuline présentent des expressions cliniques hétérogènes. Leur reconnaissance, leur diagnostic et leur prise en charge précoces sont nécessaires pour éviter les complications à long terme. OBJECTIF :Nous avons cherché à évaluer l'âge des patients au moment où ils sont adressés dans notre centre national de référence en France et le temps écoulé entre les premiers symptômes et le diagnostic et l'accès à des soins spécialisés. PATIENTS et METHODES :Nous avons analysé les données des patients atteints de syndromes rares de lipodystrophie et d'insulino-résistance adressés au centre de référence PRISIS coordonnateur (service d'endocrinologie adulte, hôpital Saint-Antoine, AP-HP, Paris), enregistrés prospectivement entre 2018 et 2023 dans la Banque Nationale de Données Maladies Rares (BNDMR). RÉSULTATS :Une cohorte de 292 patients a été analysée, dont 208 femmes, avec les diagnostics suivants : LipoDystrophie partielle familiale (FPLD, n = 124, dont n = 67 FPLD2/syndrome de Dunnigan) ; syndromes de lipodystrophie acquise (n = 98, dont n = 13 lipodystrophie généralisée acquise, AGL) ; Adénolipomatose cervicale symétrique (n = 27, syndrome de Launois-Bensaude, LB), lipodystrophie congénitale généralisée (n = 18, CGL) et autres syndromes rares de résistance sévère à l'insuline (n = 25). L'âge médian au moment de la consultation était de 47,6 ans [IQR : 31-60], allant de 25,2 ans (CGL) à 62,2 ans (LB). L'âge médian des premiers symptômes (27,6 ans [IQR : 16,8-42,0]) et le délai médian de diagnostic (6,4 ans [IQR : 1,3-19,5]) varient d'un groupe de diagnostic à l'autre. L'expression sexe-spécifique de la lipodystrophie est bien illustrée dans le groupe FPLD2 (91% de femmes), présentant les premiers signes à 19,3 ans [IQR : 14,4-27,8] avec un retard diagnostic de 10,5 ans [IQR : 1,8-27,0].CONCLUSION :La base de données nationale sur les maladies rares constitue un outil important pour l'évaluation des parcours de soins des patients atteints de lipodystrophies et de syndromes rares de résistance à l'insuline en France. L'amélioration des connaissances pour réduire le retard diagnostique est un objectif important du centre de référence PRISIS

Molecular and Cellular Bases of Lipodystrophy Syndromes

International audienceLipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed

Therapeutic indications and metabolic effects of metreleptin in patients with lipodystrophy syndromes: Real-life experience from a national reference network

International audienceAim: To describe baseline characteristics and follow-up data in patients with lipodystrophy syndromes treated with metreleptin in a national reference network, in a real-life setting.Patients and methods: Clinical and metabolic data from patients receiving metreleptin in France were retrospectively collected, at baseline, at 1 year and at the latest follow-up during treatment.Results: Forty-seven patients with lipodystrophy including generalized lipodystrophy (GLD; n = 28) and partial lipodystrophy (PLD; n = 19) received metreleptin over the last decade. At baseline, the median (interquartile range [IQR]) patient age was 29.3 (16.6-47.6) years, body mass index was 23.8 (21.2-25.7) kg/m2 and serum leptin was 3.2 (1.0-4.9) ng/mL, 94% of patients had diabetes (66% insulin-treated), 53% had hypertension and 87% had dyslipidaemia. Metreleptin therapy, administered for a median (IQR) of 31.7 (14.2-76.0) months, was ongoing in 77% of patients at the latest follow-up. In patients with GLD, glycated haemoglobin (HbA1c) and fasting triglyceride levels significantly decreased from baseline to 1 year of metreleptin treatment, from 8.4 (6.5-9.9)% [68 (48-85) mmol/mol] to 6.8 (5.6-7.4)% [51(38-57) mmol/mol], and 3.6 (1.7-8.5) mmol/L to 2.2 (1.1-3.7) mmol/L, respectively (P < 0.001), with sustained efficacy thereafter. In patients with PLD, HbA1c was not significantly modified (7.7 [7.1-9.1]% [61 (54-76) mmol/mol] at baseline vs. 7.7 [7.4-9.5]% [61(57-80) mmol/mol] at 1 year), and the decrease in fasting triglycerides (from 3.3 [1.9-9.9] mmol/L to 2.5 [1.6-5.3] mmol/L; P < 0.01) was not confirmed at the latest assessment (5.2 [2.2-11.3] mmol/L). However, among PLD patients, at 1 year, 61% were responders regarding glucose homeostasis, with lower baseline leptin levels compared to nonresponders, and 61% were responders regarding triglyceridaemia. Liver enzymes significantly decreased only in the GLD group.Conclusions: In this real-life setting study, metabolic outcomes are improved by metreleptin therapy in patients with GLD. The therapeutic indication for metreleptin needs to be clarified in patients with PLD