title: Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model.
abstract: Spinocerebellar ataxia type 28 (SCA28) is a neurodegenerative disease caused by mutations of the mitochondrial protease AFG3L2. The SCA28 mouse model, which is haploinsufficient for Afg3l2, exhibits a progressive decline in motor function and displays dark degeneration of Purkinje cells (PC-DCD) of mitochondrial origin. Here, we determined that mitochondria in cultured Afg3l2-deficient PCs ineffectively buffer evoked Ca²⁺ peaks, resulting in enhanced cytoplasmic Ca²⁺ concentrations, which subsequently triggers PC-DCD. This Ca²⁺-handling defect is the result of negative synergism between mitochondrial depolarization and altered organelle trafficking to PC dendrites in Afg3l2-mutant cells. In SCA28 mice, partial genetic silencing of the metabotropic glutamate receptor mGluR1 decreased Ca²⁺ influx in PCs and reversed the ataxic phenotype. Moreover, administration of the β-lactam antibiotic ceftriaxone, which promotes synaptic glutamate clearance, thereby reducing Ca²⁺ influx, improved ataxia-associated phenotypes in SCA28 mice when given either prior to or after symptom onset. Together, the results of this study indicate that ineffective mitochondrial Ca²⁺ handling in PCs underlies SCA28 pathogenesis and suggest that strategies that lower glutamate stimulation of PCs should be further explored as a potential treatment for SCA28 patients.
authors.forename: Francesca
authors.initials: F
authors.lastname: Maltecca
authors.forename: Elisa
authors.initials: E
authors.lastname: Baseggio
authors.forename: Francesco
authors.initials: F
authors.lastname: Consolato
authors.forename: Davide
authors.initials: D
authors.lastname: Mazza
authors.forename: Paola
authors.initials: P
authors.lastname: Podini
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Young
authors.forename: Ilaria
authors.initials: I
authors.lastname: Drago
authors.forename: Ben A
authors.initials: BA
authors.lastname: Bahr
authors.forename: Aldamaria
authors.initials: A
authors.lastname: Puliti
authors.forename: Franca
authors.initials: F
authors.lastname: Codazzi
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Casari
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics / Q000378:metabolism; D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002443:Ceftriaxone / Q000494:pharmacology / Q000627:therapeutic use; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D011597:Psychomotor Performance; D011689:Purkinje Cells / Q000502:physiology*; D020754:Spinocerebellar Ataxias / Q000151:congenital; D013132:Spinocerebellar Degenerations / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D002443:Ceftriaxone; D049069:ATP-Dependent Proteases; C542395:Afg3l2 protein, mouse; D000074183:ATPases Associated with Diverse Cellular Activities; D002118:Calcium