Human Molecular Genetics Advance Access originally published online on March 16, 2009
Human Molecular Genetics 2009 18(11):2001-2013; doi:10.1093/hmg/ddp124
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Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration
1 Division of Biochemistry and Genetics, Istituto Neurologico ‘C. Besta’, Milan, Italy 2 Human Molecular Genetics Unit, San Raffaele Scientific Institute, Milan, Italy 3 Institute of Experimental Neurology and Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy 4 The Jackson Laboratory, Bar Harbor, ME 04609, USA 5 Vita-Salute San Raffaele University, School of Medicine, Milan, Italy 6 Department of Neuroscience and Medical Biotechnologies, University of Milano-Bicocca, Milan, Italy
* To whom correspondence should be addressed at: Division of Biochemistry and Genetics, Istituto Neurologico ‘C. Besta’, via Temolo 4 20126, Milano, Italy. Tel: +39 0223942614; Fax: +39 0223942619; Email: rugarli{at}istituto-besta.it; elena.rugarli{at}unimib.it
Received February 9, 2009; Revised March 5, 2009; Accepted March 12, 2009
The mitochondrial m-AAA protease has a crucial role in axonal development and maintenance. Human mitochondria possess two m-AAA protease isoenzymes: a hetero-oligomeric complex, composed of paraplegin and AFG3L2 (Afg3 like 2), and a homo-oligomeric AFG3L2 complex. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons. Spg7–/– mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. In contrast, Afg3l2Emv66/Emv66 mutant mice, lacking the AFG3L2 protein, are affected by a severe neuromuscular phenotype, due to defects in motor axon development. The role of the homo-oligomeric m-AAA protease and the extent of cooperation and redundancy between the two isoenzymes in adult neurons are still unclear. Here we report an early-onset severe neurological phenotype in Spg7–/– Afg3l2Emv66/+ mice, characterized by loss of balance, tremor and ataxia. Spg7–/– Afg3l2Emv66/+ mice display acceleration and worsening of the axonopathy observed in paraplegin-deficient mice. In addition, they show prominent cerebellar degeneration with loss of Purkinje cells and parallel fibers, and reactive astrogliosis. Mitochondria from affected tissues are prone to lose mt-DNA and have unstable respiratory complexes. At late stages, neurons contain structural abnormal mitochondria defective in COX-SDH reaction. Our data demonstrate genetic interaction between the m-AAA isoenzymes and suggest that different neuronal populations have variable thresholds of susceptibility to reduced levels of the m-AAA protease. Moreover, they implicate impaired mitochondrial proteolysis as a novel pathway in cerebellar degeneration.
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