title: Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.
abstract: 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.
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Di Bella
authors.forename: Federico
authors.initials: F
authors.lastname: Lazzaro
authors.forename: Alfredo
authors.initials: A
authors.lastname: Brusco
authors.forename: Massimo
authors.initials: M
authors.lastname: Plumari
authors.forename: Giorgio
authors.initials: G
authors.lastname: Battaglia
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
authors.forename: Adele
authors.initials: A
authors.lastname: Finardi
authors.forename: Claudia
authors.initials: C
authors.lastname: Cagnoli
authors.forename: Filippo
authors.initials: F
authors.lastname: Tempia
authors.forename: Marina
authors.initials: M
authors.lastname: Frontali
authors.forename: Liana
authors.initials: L
authors.lastname: Veneziano
authors.forename: Tiziana
authors.initials: T
authors.lastname: Sacco
authors.forename: Enrica
authors.initials: E
authors.lastname: Boda
authors.forename: Alessandro
authors.initials: A
authors.lastname: Brussino
authors.forename: Florian
authors.initials: F
authors.lastname: Bonn
authors.forename: Barbara
authors.initials: B
authors.lastname: Castellotti
authors.forename: Silvia
authors.initials: S
authors.lastname: Baratta
authors.forename: Caterina
authors.initials: C
authors.lastname: Mariotti
authors.forename: Cinzia
authors.initials: C
authors.lastname: Gellera
authors.forename: Valentina
authors.initials: V
authors.lastname: Fracasso
authors.forename: Stefania
authors.initials: S
authors.lastname: Magri
authors.forename: Thomas
authors.initials: T
authors.lastname: Langer
authors.forename: Paolo
authors.initials: P
authors.lastname: Plevani
authors.forename: Stefano
authors.initials: S
authors.lastname: Di Donato
authors.forename: Marco
authors.initials: M
authors.lastname: Muzi-Falconi
authors.forename: Franco
authors.initials: F
authors.lastname: Taroni
mesh_terms: D049069:ATP-Dependent Proteases; D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D019069:Cell Respiration; D002531:Cerebellum / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005816:Genetic Complementation Test; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011689:Purkinje Cells / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013132:Spinocerebellar Degenerations / Q000235:genetics*
chemical_list: D003576:Electron Transport Complex IV; D049069:ATP-Dependent Proteases; C120699:AFG3L2 protein, human; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities