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Mice harbouring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity
- Source :
- Neurobiology of Disease, Vol 124, Iss, Pp 14-28 (2019)
- Publication Year :
- 2019
- Publisher :
- Academic Press Inc., 2019.
-
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 signs of ataxia were detectable by beam test at 18 months. Cerebellar pathology was negative; electrophysiological analysis showed increased spontaneous firing in Purkinje cells from heterozygous mutants with respect to wild-type controls, although not statistically significant. 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 also altered, in line with greatly reduced expression of Opa1 fusogenic protein L-isoforms. The mitochondrial alterations observed in MEFs were also detected in cerebella of 18-month-old heterozygous mutants, suggesting they 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.
- Subjects :
- 0301 basic medicine
Ataxia
Mutant
Mutation, Missense
Biology
medicine.disease_cause
Proteotoxicity
lcsh:RC321-571
Mitochondrial Proteins
03 medical and health sciences
Purkinje Cells
SCA28
0302 clinical medicine
ATP-Dependent Proteases
Mitochondrial dynamic
medicine
Missense mutation
Animals
Spinocerebellar Ataxias
Gene Knock-In Techniques
Allele
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
AFG3L2
030304 developmental biology
Membrane Potential, Mitochondrial
0303 health sciences
Mutation
Cerebellar ataxia
Mouse knock-in
medicine.disease
Molecular biology
Phenotype
Mitochondria
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
Neurology
SCA28 AFG3L2 Mouse knock-in Mitochondrial dynamics Proteotoxicity
Spinocerebellar ataxia
Mitochondrial dynamics
ATPases Associated with Diverse Cellular Activities
Female
medicine.symptom
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Neurobiology of Disease, Vol 124, Iss, Pp 14-28 (2019)
- Accession number :
- edsair.doi.dedup.....d3e06baf3cba810a71d3151e5fd4dbb9