title: Haploinsufficiency of AFG3L2, the gene responsible for spinocerebellar ataxia type 28, causes mitochondria-mediated Purkinje cell dark degeneration.
abstract: Paraplegin and AFG3L2 are ubiquitous nuclear-encoded mitochondrial proteins that form hetero-oligomeric paraplegin-AFG3L2 and homo-oligomeric AFG3L2 complexes in the inner mitochondrial membrane, named m-AAA proteases. These complexes ensure protein quality control in the inner membrane, jointly with a chaperone-like activity on the respiratory chain complexes. Despite coassembling in the same complex, mutations of either paraplegin or AFG3L2 cause two different neurodegenerative disorders. Indeed, mutations of paraplegin are responsible for a recessive form of hereditary spastic paraplegia, whereas mutations of AFG3L2 have been recently associated to a dominant form of spinocerebellar ataxia (SCA28). In this work, we report that the mouse model haploinsufficient for Afg3l2 recapitulates important pathophysiological features of the human disease, thus representing the first SCA28 model. Furthermore, we propose a pathogenetic mechanism in which respiratory chain dysfunction and increased reactive oxygen species production caused by Afg3l2 haploinsufficiency lead to dark degeneration of Purkinje cells and cerebellar dysfunction.
authors.affiliation: Center for Genomics, Bioinformatics, and Biostatistics, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Maltecca
authors.forename: Raffaella
authors.initials: R
authors.lastname: Magnoni
authors.forename: Federica
authors.initials: F
authors.lastname: Cerri
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Casari
mesh_terms: D049069:ATP-Dependent Proteases; D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002531:Cerebellum / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005911:Gliosis / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000473:pathology / Q000502:physiology*; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D011689:Purkinje Cells / Q000473:pathology / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*
chemical_list: D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D049069:ATP-Dependent Proteases; C542395:Afg3l2 protein, mouse; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities