Restoring calcium homeostasis in Purkinje cells arrests neurodegeneration and neuroinflammation in the ARSACS mouse model

Andrea Del Bondio; Fabiana Longo; Daniele De Ritis; Erica Spirito; Paola Podini; Bernard Brais; Angela Bachi; Angelo Quattrini; Francesca Maltecca

doi:10.1172/jci.insight.163576

Restoring calcium homeostasis in Purkinje cells arrests neurodegeneration and neuroinflammation in the ARSACS mouse model

Andrea Del Bondio,¹ Fabiana Longo,¹ Daniele De Ritis,¹ Erica Spirito,¹ Paola Podini,² Bernard Brais,³ Angela Bachi,⁴ Angelo Quattrini,² and Francesca Maltecca¹

Published May 9, 2023 - More info

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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). 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.

Restoring calcium homeostasis in Purkinje cells arrests neurodegeneration and neuroinflammation in the ARSACS mouse model

Andrea Del Bondio,¹ Fabiana Longo,¹ Daniele De Ritis,¹ Erica Spirito,¹ Paola Podini,² Bernard Brais,³ Angela Bachi,⁴ Angelo Quattrini,² and Francesca Maltecca¹

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Restoring calcium homeostasis in Purkinje cells arrests neurodegeneration and neuroinflammation in the ARSACS mouse model

Andrea Del Bondio,1 Fabiana Longo,1 Daniele De Ritis,1 Erica Spirito,1 Paola Podini,2 Bernard Brais,3 Angela Bachi,4 Angelo Quattrini,2 and Francesca Maltecca1

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Andrea Del Bondio,¹ Fabiana Longo,¹ Daniele De Ritis,¹ Erica Spirito,¹ Paola Podini,² Bernard Brais,³ Angela Bachi,⁴ Angelo Quattrini,² and Francesca Maltecca¹