Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28

Nat Genet. 2010 Apr;42(4):313-21. doi: 10.1038/ng.544. Epub 2010 Mar 7.


Autosomal dominant spinocerebellar ataxias (SCAs) are genetically heterogeneous neurological disorders characterized by cerebellar dysfunction mostly due to Purkinje cell degeneration. Here we show that AFG3L2 mutations cause SCA type 28. Along with paraplegin, which causes recessive spastic paraplegia, AFG3L2 is a component of the conserved m-AAA metalloprotease complex involved in the maintenance of the mitochondrial proteome. We identified heterozygous missense mutations in five unrelated SCA families and found that AFG3L2 is highly and selectively expressed in human cerebellar Purkinje cells. m-AAA-deficient yeast cells expressing human mutated AFG3L2 homocomplex show respiratory deficiency, proteolytic impairment and deficiency of respiratory chain complex IV. Structure homology modeling indicates that the mutations may affect AFG3L2 substrate handling. This work identifies AFG3L2 as a novel cause of dominant neurodegenerative disease and indicates a previously unknown role for this component of the mitochondrial protein quality control machinery in protecting the human cerebellum against neurodegeneration.

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
  • Base Sequence
  • Cell Respiration
  • Cerebellum / metabolism
  • Electron Transport Complex IV / metabolism
  • Genetic Complementation Test
  • Humans
  • Molecular Sequence Data
  • Mutation, Missense*
  • Purkinje Cells / metabolism
  • Saccharomyces cerevisiae / genetics
  • Spinocerebellar Degenerations / genetics*


  • Electron Transport Complex IV
  • ATP-Dependent Proteases
  • AFG3L2 protein, human
  • Adenosine Triphosphatases
  • ATPases Associated with Diverse Cellular Activities