Haploinsufficiency of AFG3L2, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration

• Published in: The Journal of neuroscience Vol. 29; no. 29; pp. 9244 - 9254
• Main Authors: Maltecca, Francesca, Magnoni, Raffaella, Cerri, Federica, Cox, Gregory A, Quattrini, Angelo, Casari, Giorgio
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 22-07-2009; Society for Neuroscience
• Subjects: Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Adenosine Triphosphate - metabolism; Aging; Animals; Apoptosis - physiology; ATP-Dependent Proteases; ATPases Associated with Diverse Cellular Activities; Cerebellum - pathology; Cerebellum - physiopathology; Disease Models, Animal; Ganglia, Spinal - cytology; Ganglia, Spinal - metabolism; Ganglia, Spinal - pathology; Gliosis - pathology; Gliosis - physiopathology; Mice; Mice, Mutant Strains; Mitochondria - pathology; Mitochondria - physiology; Motor Activity - genetics; Motor Activity - physiology; Motor Neurons - cytology; Motor Neurons - metabolism; Nerve Degeneration - pathology; Nerve Degeneration - physiopathology; Purkinje Cells - pathology; Purkinje Cells - physiology; Reactive Oxygen Species - metabolism; Spinal Cord - cytology; Spinal Cord - metabolism; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - pathology; Spinocerebellar Ataxias - physiopathology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1532-09.2009

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.