RT Journal Article
SR Electronic
T1 Haploinsufficiency of <em>AFG3L2</em>, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9244
OP 9254
DO 10.1523/JNEUROSCI.1532-09.2009
VO 29
IS 29
A1 Francesca Maltecca
A1 Raffaella Magnoni
A1 Federica Cerri
A1 Gregory A. Cox
A1 Angelo Quattrini
A1 Giorgio Casari
YR 2009
UL http://www.jneurosci.org/content/29/29/9244.abstract
AB 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.