ArticleJCI insight2023
Restoring calcium homeostasis in Purkinje cells arrests neurodegeneration and neuroinflammation in the ARSACS mouse model.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 24 citations in OpenAlex.
- The role of impaired mitochondrial function in neurological manifestations of mitochondrial diseases.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- Loss of SARM1 Improves Phenotypes in a Mouse Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.Neurology. Genetics · 2026Article
- Evaluation of modafinil's neuroprotective effects in lipopolysaccharide-induced sepsis-associated encephalopathy: associations with GSK3β, inflammatory, oxidative stress, and apoptotic signaling.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Cerebroprotective potential of ceftriaxone against cadmium chloride-induced cerebral inflammatory changes and oxidative insult.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- CALB2 Overexpression Attenuates Neuropathic Pain by Inhibiting Oxidative Stress and Modulating Microglia M1/M2 Polarization Through Activation of the cAMP/CREB Pathway.Neurochemical research · 2025Article
- Autosomal Recessive Cerebellar Ataxias: Translating Genes to Therapies.Annals of neurology · 2025Review
- S100B Mitigates Cytoskeletal and Mitochondrial Alterations in a Glial Cell Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.Molecular neurobiology · 2025Article
- Selection of Clinical Outcome Assessments for Trial Readiness in ARSACS - 2-year Progression and Responsiveness to Change Part 1: Disease Severity, Swallowing, Upper Limb Function, and Participation.Cerebellum (London, England) · 2025Article
- Genetic analysis of three patients from two unrelated Chinese families with autosomal recessive spastic ataxia of Charlevoix-Saguenay.BMC medical genomics · 2025Article
- Longitudinal Imaging Biomarkers Correlate with Progressive Motor Deficit in the Mouse Model of Charlevoix-Saguenay Ataxia.Annals of neurology · 2025Article
- Whole Blood DNA Methylation Analysis Reveals Epigenetic Changes Associated with ARSACS.Cerebellum (London, England) · 2025Article
- Editorial: Translational research in hereditary spastic paraplegias: filling the diagnosis gap and therapeutic perspectives.Frontiers in neuroscience · 2025Article
- The Potential of Mesenchymal Stem Cells in Treating Spinocerebellar Ataxia: Advances and Future Directions.Biomedicines · 2024Review
- Toll-like receptor 4 deficiency in Purkinje neurons drives cerebellar ataxia by impairing the BK channel-mediated after-hyperpolarization and cytosolic calcium homeostasis.Cell death & disease · 2024Article
- Review
- Reduction of sacsin levels in peripheral blood mononuclear cells as a diagnostic tool for spastic ataxia of Charlevoix-Saguenay.Brain communications · 2024Article
- Proteomics and lipidomic analysis reveal dysregulated pathways associated with loss of sacsin.Frontiers in neuroscience · 2024Article
- A Novel Mutation in Sacsin, p.Val1335IIe, May Cause Late-Onset Sacsinopathy Due to Haploinsufficiency.Current issues in molecular biology · 2023Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in SACS gene encoding sacsin, a huge protein highly expressed in cerebellar Purkinje cells (PCs). Patients with ARSACS, as well as mouse models, display early degeneration of PCs, but the underlying mechanisms remain unexplored, with no available treatments. In this work, we demonstrated aberrant calcium (Ca2+) homeostasis and its impact on PC degeneration in ARSACS. Mechanistically, we found pathological elevation in Ca2+-evoked responses in Sacs-/- PCs as the result of defective mitochondria and ER trafficking to distal dendrites and strong downregulation of key Ca2+ buffer proteins. Alteration of cytoskeletal linkers, which we identified as specific sacsin interactors, likely account for faulty organellar trafficking in Sacs-/- cerebellum. Based on this pathogenetic cascade, we treated Sacs-/- mice with Ceftriaxone, a repurposed drug that exerts neuroprotection by limiting neuronal glutamatergic stimulation and, thus, Ca2+ fluxes into PCs. Ceftriaxone treatment significantly improved motor performances of Sacs-/- mice, at both pre- and postsymptomatic stages. We correlated this effect to restored Ca2+ homeostasis, which arrests PC degeneration and attenuates secondary neuroinflammation. These findings disclose key steps in ARSACS pathogenesis and support further optimization of Ceftriaxone in preclinical and clinical settings for the treatment of patients with ARSACS.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.