Mice harbouring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity
Articolo
Data di Pubblicazione:
2019
Citazione:
Mice harbouring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity / C. Mancini, E. Hoxha, L. Iommarini, A. Brussino, U. Richter, F. Montarolo, C. Cagnoli, R. Parolisi, D.I. Gondor Morosini, V. Nicolo, F. Maltecca, L. Muratori, G. Ronchi, S. Geuna, F. Arnaboldi, E. Donetti, E. Giorgio, S. Cavalieri, E. Di Gregorio, E. Pozzi, M. Ferrero, E. Riberi, G. Casari, F. Altruda, E. Turco, G. Gasparre, B.J. Battersby, A.M. Porcelli, E. Ferrero, A. Brusco, F. Tempia. - In: NEUROBIOLOGY OF DISEASE. - ISSN 1095-953X. - 124(2019 Apr), pp. 14-28.
Abstract:
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 Opa1 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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
SCA28; AFG3L2; mouse knock-in; mitochondrial dynamics; proteotoxicity
Elenco autori:
C. Mancini, E. Hoxha, L. Iommarini, A. Brussino, U. Richter, F. Montarolo, C. Cagnoli, R. Parolisi, D.I. Gondor Morosini, V. Nicolo, F. Maltecca, L. Muratori, G. Ronchi, S. Geuna, F. Arnaboldi, E. Donetti, E. Giorgio, S. Cavalieri, E. Di Gregorio, E. Pozzi, M. Ferrero, E. Riberi, G. Casari, F. Altruda, E. Turco, G. Gasparre, B.J. Battersby, A.M. Porcelli, E. Ferrero, A. Brusco, F. Tempia
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