{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:53:21Z","timestamp":1790837601114,"version":"4.1.0"},"reference-count":55,"publisher":"American Society for Clinical Investigation","issue":"12","license":[{"start":{"date-parts":[[2023,6,22]],"date-time":"2023-06-22T00:00:00Z","timestamp":1687392000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"crossref","award":["RF-2016-02361610"],"award-info":[{"award-number":["RF-2016-02361610"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"crossref","award":["RF-2019-12370417"],"award-info":[{"award-number":["RF-2019-12370417"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"crossref","award":["Joint Programme on Rare Diseases 2021,grant Treat-ARCA"],"award-info":[{"award-number":["Joint Programme on Rare Diseases 2021,grant Treat-ARCA"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ataxia Charlevoix-Saguenay Foundation","award":["ARSACS MAL19"],"award-info":[{"award-number":["ARSACS MAL19"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,22]]},"abstract":"<jats:p>\n                    Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in\n                    <jats:italic>SACS<\/jats:italic>\n                    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 (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ) homeostasis and its impact on PC degeneration in ARSACS. Mechanistically, we found pathological elevation in Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -evoked responses in\n                    <jats:italic>\n                      Sacs\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    PCs as the result of defective mitochondria and ER trafficking to distal dendrites and strong downregulation of key Ca\n                    <jats:sup>2+<\/jats:sup>\n                    buffer proteins. Alteration of cytoskeletal linkers, which we identified as specific sacsin interactors, likely account for faulty organellar trafficking in\n                    <jats:italic>\n                      Sacs\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    cerebellum. Based on this pathogenetic cascade, we treated\n                    <jats:italic>\n                      Sacs\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    mice with Ceftriaxone, a repurposed drug that exerts neuroprotection by limiting neuronal glutamatergic stimulation and, thus, Ca\n                    <jats:sup>2+<\/jats:sup>\n                    fluxes into PCs. Ceftriaxone treatment significantly improved motor performances of\n                    <jats:italic>\n                      Sacs\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    mice, at both pre- and postsymptomatic stages. We correlated this effect to restored Ca\n                    <jats:sup>2+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.163576","type":"journal-article","created":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T13:18:43Z","timestamp":1683638323000},"source":"Crossref","is-referenced-by-count":28,"title":["Restoring calcium homeostasis in Purkinje cells arrests neurodegeneration and neuroinflammation in the ARSACS mouse model"],"prefix":"10.1172","volume":"8","author":[{"given":"Andrea","family":"Del Bondio","sequence":"first","affiliation":[{"name":"Mitochondrial Dysfunctions in Neurodegeneration Unit, Division of Neuroscience, Ospedale San Raffaele, Milan, 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