title: Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration.
abstract: 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, Afg3l2(Emv66/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(-/-) Afg3l2(Emv66/+) mice, characterized by loss of balance, tremor and ataxia. Spg7(-/-) Afg3l2(Emv66/+) 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.
authors.affiliation: Division of Biochemistry and Genetics, Istituto Neurologico C. Besta, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Martinelli
authors.forename: Veronica
authors.initials: V
authors.lastname: La Mattina
authors.forename: Andrea
authors.initials: A
authors.lastname: Bernacchia
authors.forename: Raffaella
authors.initials: R
authors.lastname: Magnoni
authors.forename: Federica
authors.initials: F
authors.lastname: Cerri
authors.forename: Gregory
authors.initials: G
authors.lastname: Cox
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Casari
authors.forename: Elena I
authors.initials: EI
authors.lastname: Rugarli
mesh_terms: D049069:ATP-Dependent Proteases; D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000201:enzymology / Q000502:physiology; D002526:Cerebellar Diseases / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D011485:Protein Binding; D015419:Spastic Paraplegia, Hereditary / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology
chemical_list: D007527:Isoenzymes; D049069:ATP-Dependent Proteases; C542395:Afg3l2 protein, mouse; D008666:Metalloendopeptidases; C491813:Spg7 protein, mouse; C114583:m-AAA proteases; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities