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  • Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation

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Neurogenetics
Original article
Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation
  1. Susanna Tulli1,
  2. Andrea Del Bondio1,
  3. Valentina Baderna1,
  4. Davide Mazza2,
  5. Franca Codazzi3,4,
  6. Tyler Mark Pierson5,
  7. Alessandro Ambrosi3,
  8. Dagmar Nolte6,
  9. Cyril Goizet7,8,
  10. Camilo Toro9,
  11. Jonathan Baets10,11,
  12. Tine Deconinck10,11,
  13. Peter DeJonghe10,11,
  14. Paola Mandich12,
  15. Giorgio Casari3,13,
  16. Francesca Maltecca1,3
  1. 1 Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
  2. 2 Experimental Imaging Center, IRCCS Ospedale San Raffaele, Milan, Italy
  3. 3 Università Vita-Salute San Raffaele, Milan, Italy
  4. 4 Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy
  5. 5 Departments of Pediatrics and Neurology and the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  6. 6 Department of Medicine, Institute for Human Genetics, Justus-Liebig-University Giessen, Giessen, Germany
  7. 7 Centre de Reference Neurogenetique, Service de Genetique Medicale, CHU Bordeaux, Bordeaux, France
  8. 8 Laboratoire MRGM, INSERM U1211, Bordeaux, France
  9. 9 Undiagnosed Disease Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA
  10. 10 Neurogenetics Group and Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
  11. 11 Neuromuscular Reference Centre, Antwerp University Hospital, Antwerpen, Belgium
  12. 12 DINOGMI, University of Genoa and IRCCS Ospedale Policlinico San Martino, Genoa, Italy
  13. 13 Telethon Institute of Genetics and Medicine, Naples, Italy
  1. Correspondence to Dr Francesca Maltecca, Division of Genetics and Cell Biology IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Via Olgettina 58, Milan 20132, Italy; maltecca.francesca{at}hsr.it

Abstract

Background Spinocerebellar ataxia type 28 (SCA28) is a dominantly inherited neurodegenerative disease caused by pathogenic variants in AFG3L2. The AFG3L2 protein is a subunit of mitochondrial m-AAA complexes involved in protein quality control. Objective of this study was to determine the molecular mechanisms of SCA28, which has eluded characterisation to date.

Methods We derived SCA28 patient fibroblasts carrying different pathogenic variants in the AFG3L2 proteolytic domain (missense: the newly identified p.F664S and p.M666T, p.G671R, p.Y689H and a truncating frameshift p.L556fs) and analysed multiple aspects of mitochondrial physiology. As reference of residual m-AAA activity, we included SPAX5 patient fibroblasts with homozygous p.Y616C pathogenic variant, AFG3L2+/− HEK293 T cells by CRISPR/Cas9-genome editing and Afg3l2 −/− murine fibroblasts.

Results We found that SCA28 cells carrying missense changes have normal levels of assembled m-AAA complexes, while the cells with a truncating pathogenic variant had only half of this amount. We disclosed inefficient mitochondrial fusion in SCA28 cells caused by increased OPA1 processing operated by hyperactivated OMA1. Notably, we found altered mitochondrial proteostasis to be the trigger of OMA1 activation in SCA28 cells, with pharmacological attenuation of mitochondrial protein synthesis resulting in stabilised levels of OMA1 and OPA1 long forms, which rescued mitochondrial fusion efficiency. Secondary to altered mitochondrial morphology, mitochondrial calcium uptake resulted decreased in SCA28 cells.

Conclusion Our data identify the earliest events in SCA28 pathogenesis and open new perspectives for therapy. By identifying similar mitochondrial phenotypes between SCA28 cells and AFG3L2+/− cells, our results support haploinsufficiency as the mechanism for the studied pathogenic variants.

  • genetics
  • molecular genetics
  • movement disorders (other than parkinsons)
  • mitochondria
  • cell biology

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jmedgenet-2018-105766

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    Footnotes

    • ST and ADB contributed equally.

    • Contributors FM and GC conceived the study, interpreted the results and wrote the manuscript. TMP revised and edited the manuscript. ST and ADB performed the experiments, analysed data and helped writing the manuscript. VB, DM and FC performed the experiments. AA performed statistical analysis of data. DN, CG, TMP, CT, JB, TD, PD and PM provided primary fibroblasts or skin biopsies from patients. All authors critically discussed the data.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Ethics approval The local institutional review boards approved this study.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Patient consent for publication Not required.