Mice harbouring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity

NEUROBIOLOGY OF DISEASE

卷:124

Article

Mancini, Cecilia¹  Hoxha, Eriola^2,3  Iommarini, Luisa⁴  Brussino, Alessandro¹  Richter, Uwe⁵  Montarolo, Francesca^2,3  Cagnoli, Claudia¹  Parolisi, Roberta^2,3  Morosini, Diana Iulia Gondor^2,3  Nicolo, Valentina^2,3  Maltecca, Francesca⁶  Muratori, Luisa^3,7  Ronchi, Giulia^3,7  Geuna, Stefano^3,7  Arnaboldi, Francesca⁸  Donetti, Elena⁸  Giorgio, Elisa¹  Cavalieri, Simona¹  Di Gregorio, Eleonora⁹  Pozzi, Elisa¹  Ferrero, Marta¹  Riberi, Evelise¹⁰  Casari, Giorgio⁶  Altruda, Fiorella¹¹  Turco, Emilia¹¹  Gasparre, Giuseppe¹²  Battersby, Brendan J.⁵  Porcelli, Anna Maria⁴  Ferrero, Enza¹  Brusco, Alfredo^1,9,12  Tempia, Filippo^2,3,12 

[1] Univ Torino, Dept Med Sci, Via Santena 19, I-10126 Turin, Italy

[2] Univ Torino, Dept Neurosci, Turin, Italy

[3] NICO, Orbassano, Italy

[4] Univ Bologna, FABIT, Dept Pharm & Biotechnol, Bologna, Italy

[5] Univ Helsinki, Inst Biotechnol, Helsinki, Finland

[6] Univ Vita Salute San Raffaele, San Raffaele Sci Inst, Div Genet & Cell Biol, Milan, Italy

[7] Univ Torino, Dept Clin & Biol Sci, Turin, Italy

[8] Univ Milan, Dept Biomed Sci Hlth, Milan, Italy

[9] Citta Salute & Sci Univ Hosp, Med Genet Unit, Turin, Italy

[10] Univ Torino, Dept Publ Hlth & Pediat, Turin, Italy

[11] Univ Torino, Dept Mol Biotechnol & Hlth Sci, Mol Biotechnol Ctr, Turin, Italy

[12] Univ Bologna, Dept Med & Surg Sci, Med Genet, Bologna, Italy

关键词: SCA28;    AFG3L2;    Mouse knock-in;    Mitochondrial dynamics;    Proteotoxicity;   

DOI  :  10.1016/j.nbd.2018.10.018

来源: Elsevier

【 摘 要 】

Spinocerebellar ataxia 28 is an autosomal dominant neurodegenerative disorder caused by missense mutations affecting the proteolytic domain of AFG3L2, a major component of the mitochondrial m-AAA protease. However, little is known of the underlying pathogenetic mechanisms or how to treat patients with SCA28. Currently available Afg3l2 mutant mice harbour deletions that lead to severe, early-onset neurological phenotypes that do not faithfully reproduce the late-onset and slowly progressing SCA28 phenotype. Here we describe production and detailed analysis of a new knock-in murine model harbouring an Afg3l2 allele carrying the p.Met665Arg patient-derived mutation. Heterozygous mutant mice developed normally but adult mice showed signs of cerebellar ataxia detectable by beam test. Although cerebellar pathology was negative, electrophysiological analysis showed a trend towards increased spontaneous firing in Purkinje cells from heterozygous mutants with respect to wild-type controls. As homozygous mutants died perinatally with evidence of cardiac atrophy, for each genotype we generated mouse embryonic fibroblasts (MEFs) to investigate mitochondrial function. MEFs from mutant mice showed altered mitochondrial bioenergetics, with decreased basal oxygen consumption rate, ATP synthesis and mitochondrial membrane potential. Mitochondrial network formation and morphology was altered, with greatly reduced expression of fusogenic Opal isoforms. Mitochondrial alterations were also detected in cerebella of 18-month-old heterozygous mutants and may be a hallmark of disease. Pharmacological inhibition of de novo mitochondrial protein translation with chloramphenicol caused reversal of mitochondrial morphology in homozygous mutant MEFs, supporting the relevance of mitochondrial proteotoxicity for SCA28 pathogenesis and therapy development.

【 授权许可】

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