ResearchIn-Press PreviewCell biologyNeuroscience
Open Access | 10.1172/jci.insight.163576
1Mitochondrial Dysfunctions in Neurodegeneration Unit, Ospedale San Raffaele, Milan, Italy
2Division of Neuroscience and Institute of Experimental Neurology, Ospedale San Raffaele, Milan, Italy
3Department of Neurology and Neurosurgery, McGill University, Montréal, Canada
4Functional Proteomics Unit, IFOM- FIRC Institute of Molecular Oncology, Milan, Italy
Find articles by
Del Bondio, A.
in:
JCI
|
PubMed
|
Google Scholar
|
1Mitochondrial Dysfunctions in Neurodegeneration Unit, Ospedale San Raffaele, Milan, Italy
2Division of Neuroscience and Institute of Experimental Neurology, Ospedale San Raffaele, Milan, Italy
3Department of Neurology and Neurosurgery, McGill University, Montréal, Canada
4Functional Proteomics Unit, IFOM- FIRC Institute of Molecular Oncology, Milan, Italy
Find articles by
Longo, F.
in:
JCI
|
PubMed
|
Google Scholar
|
1Mitochondrial Dysfunctions in Neurodegeneration Unit, Ospedale San Raffaele, Milan, Italy
2Division of Neuroscience and Institute of Experimental Neurology, Ospedale San Raffaele, Milan, Italy
3Department of Neurology and Neurosurgery, McGill University, Montréal, Canada
4Functional Proteomics Unit, IFOM- FIRC Institute of Molecular Oncology, Milan, Italy
Find articles by
De Ritis, D.
in:
JCI
|
PubMed
|
Google Scholar
|
1Mitochondrial Dysfunctions in Neurodegeneration Unit, Ospedale San Raffaele, Milan, Italy
2Division of Neuroscience and Institute of Experimental Neurology, Ospedale San Raffaele, Milan, Italy
3Department of Neurology and Neurosurgery, McGill University, Montréal, Canada
4Functional Proteomics Unit, IFOM- FIRC Institute of Molecular Oncology, Milan, Italy
Find articles by Spirito, E. in: JCI | PubMed | Google Scholar
1Mitochondrial Dysfunctions in Neurodegeneration Unit, Ospedale San Raffaele, Milan, Italy
2Division of Neuroscience and Institute of Experimental Neurology, Ospedale San Raffaele, Milan, Italy
3Department of Neurology and Neurosurgery, McGill University, Montréal, Canada
4Functional Proteomics Unit, IFOM- FIRC Institute of Molecular Oncology, Milan, Italy
Find articles by Podini, P. in: JCI | PubMed | Google Scholar
1Mitochondrial Dysfunctions in Neurodegeneration Unit, Ospedale San Raffaele, Milan, Italy
2Division of Neuroscience and Institute of Experimental Neurology, Ospedale San Raffaele, Milan, Italy
3Department of Neurology and Neurosurgery, McGill University, Montréal, Canada
4Functional Proteomics Unit, IFOM- FIRC Institute of Molecular Oncology, Milan, Italy
Find articles by Brais, B. in: JCI | PubMed | Google Scholar
1Mitochondrial Dysfunctions in Neurodegeneration Unit, Ospedale San Raffaele, Milan, Italy
2Division of Neuroscience and Institute of Experimental Neurology, Ospedale San Raffaele, Milan, Italy
3Department of Neurology and Neurosurgery, McGill University, Montréal, Canada
4Functional Proteomics Unit, IFOM- FIRC Institute of Molecular Oncology, Milan, Italy
Find articles by
Bachi, A.
in:
JCI
|
PubMed
|
Google Scholar
|
1Mitochondrial Dysfunctions in Neurodegeneration Unit, Ospedale San Raffaele, Milan, Italy
2Division of Neuroscience and Institute of Experimental Neurology, Ospedale San Raffaele, Milan, Italy
3Department of Neurology and Neurosurgery, McGill University, Montréal, Canada
4Functional Proteomics Unit, IFOM- FIRC Institute of Molecular Oncology, Milan, Italy
Find articles by Quattrini, A. in: JCI | PubMed | Google Scholar
1Mitochondrial Dysfunctions in Neurodegeneration Unit, Ospedale San Raffaele, Milan, Italy
2Division of Neuroscience and Institute of Experimental Neurology, Ospedale San Raffaele, Milan, Italy
3Department of Neurology and Neurosurgery, McGill University, Montréal, Canada
4Functional Proteomics Unit, IFOM- FIRC Institute of Molecular Oncology, Milan, Italy
Find articles by Maltecca, F. in: JCI | PubMed | Google Scholar
Published May 9, 2023 - More info
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). ARSACS patients, 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, that 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 which 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 post-symptomatic stages. We correlated this effect to restored Ca2+ homeostasis, which arrests PC degeneration and attenuates secondary neuroinflammation. These findings disclose new key steps in ARSACS pathogenesis and support further optimization of Ceftriaxone in pre-clinical and clinical settings for the treatment of ARSACS
patients.