Journal Article

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

Tempia, Filippo, Brusco, Alfredo, Mariotti, Caterina, Battaglia, Giorgio, Veneziano, Liana, Fracasso, Valentina, Sacco, Tiziana, Castellotti, Barbara, Magri, Stefania, Taroni, Franco, Gellera, Cinzia, Plevani, Paolo, Muzi-Falconi, Marco, Plumari, Massimo, Cagnoli, Claudia, Langer, Thomas, Finardi, Adele, Di Bella, Daniela, Frontali, Marina, Boda, Enrica, Baratta, Silvia, Brussino, Alessandro, Bonn, Florian, Di Donato, Stefano, Pastore, Annalisa, Lazzaro, Federico

2010

Overview

Franco Taroni and colleagues report the identification of mutations in AFG3L2 that cause dominant spinocerebellar ataxia type 28. Along with paraplegin, AFG3L2 forms a protein complex with ATPase and metalloprotease activities and functions in the maintenance of the mitochondrial proteome. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/2489/144 / 631/208/726/2129 / 631/208/737 / 631/378/1689/2014 / Adenosine Triphosphatases - genetics / Adenosine Triphosphatases - metabolism / Agriculture / Animal Genetics and Genomics / Ataxia / Ataxia telangiectasia / ATP-Dependent Proteases / ATPases Associated with Diverse Cellular Activities / Base Sequence / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell Respiration / Cerebellum - metabolism / Electron Transport Complex IV - metabolism / Gene Function / Gene mutations / Genes / Genetic aspects / Genetic Complementation Test / Genotype & phenotype / Health aspects / Human Genetics / Humans / Molecular Sequence Data / Mutation / Mutation, Missense / Physiological aspects / Proteases / Proteins / Purkinje Cells - metabolism / Quality control / Risk factors / Saccharomyces cerevisiae - genetics / Spinocerebellar Degenerations - genetics / Yeasts