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The Journal of Neuroscience, March 12, 2008, 28(11):2827-2836; doi:10.1523/JNEUROSCI.4677-07.2008

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Neurobiology of Disease
The Mitochondrial Protease AFG3L2 Is Essential for Axonal Development

Francesca Maltecca,^1 * Asadollah Aghaie,^3 * David G. Schroeder,⁴ Laura Cassina,¹ Benjamin A. Taylor,⁴ Sandra J. Phillips,⁴ Mariachiara Malaguti,² Stefano Previtali,² Jean-Louis Guénet,³ Angelo Quattrini,² Gregory A. Cox,⁴ and Giorgio Casari^1,5

¹Human Molecular Genetics Unit, and ²Neuropathology Unit and Istituto di Neurologia Sperimentale, San Raffaele Scientific Institute, 20132 Milan, Italy, ³Departement de Biologie du Developpement, Institut Pasteur, 75724 Paris Cedex 15, France, ⁴The Jackson Laboratory, Bar Harbor, Maine 04609, and ⁵Vita-Salute San Raffaele University, School of Medicine, 20132 Milan, Italy

Correspondence should be addressed to Dr. Giorgio Casari, Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy. Email: casari.giorgio{at}hsr.it

The mitochondrial metalloprotease AFG3L2 assembles with the homologous protein paraplegin to form a supracomplex in charge of the essential protein quality control within mitochondria. Mutations of paraplegin cause a specific axonal degeneration of the upper motoneuron and, therefore, hereditary spastic paraplegia. Here we present two Afg3l2 murine models: a newly developed null and a spontaneous mutant that we found carrier of a missense mutation. Contrasting with the mild and late onset axonal degeneration of paraplegin-deficient mouse, Afg3l2 models display a marked impairment of axonal development with delayed myelination and poor axonal radial growth leading to lethality at P16. The increased severity of the Afg3l2 mutants is explained by two main molecular features that differentiate AFG3L2 from paraplegin: its higher neuronal expression and its versatile ability to support both hetero-oligomerization and homo-oligomerization. Our data assign to AFG3L2 a crucial role by linking mitochondrial metabolism and axonal development. Moreover, we propose AFG3L2 as an excellent candidate for motoneuron and cerebellar diseases with early onset unknown etiology.

Key words: paraplegin; m-AAA protease; axonal development; mitochondria; neurodegeneration; spinal cord

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Received Oct. 15, 2007; revised Dec. 21, 2007; accepted Dec. 29, 2007.

Correspondence should be addressed to Dr. Giorgio Casari, Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy. Email: casari.giorgio{at}hsr.it

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