Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration

Hum Mol Genet. 2009 Jun 1;18(11):2001-13. doi: 10.1093/hmg/ddp124. Epub 2009 Mar 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Dependent Proteases
  • ATPases Associated with Diverse Cellular Activities
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Axons / enzymology
  • Axons / physiology
  • Cerebellar Diseases / enzymology*
  • Cerebellar Diseases / genetics
  • Cerebellar Diseases / physiopathology
  • Disease Models, Animal
  • Female
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Male
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / enzymology
  • Mitochondria / genetics
  • Protein Binding
  • Spastic Paraplegia, Hereditary / enzymology*
  • Spastic Paraplegia, Hereditary / genetics
  • Spastic Paraplegia, Hereditary / physiopathology

Substances

  • Isoenzymes
  • ATP-Dependent Proteases
  • Afg3l2 protein, mouse
  • Metalloendopeptidases
  • Spg7 protein, mouse
  • m-AAA proteases
  • Adenosine Triphosphatases
  • ATPases Associated with Diverse Cellular Activities