title: Altered apoptosis regulation in Kufor-Rakeb syndrome patients with mutations in the ATP13A2 gene.
abstract: ATP13A2 gene encodes for a protein of the group 5 P-type ATPase family. ATP13A2 mutations are responsible for Kufor-Rakeb syndrome (KRS), a rare autosomal recessive juvenile parkinsonism characterized by the subacute onset of extrapyramidal, pyramidal and cognitive dysfunction with secondary nonresponsiveness to levodopa. FBXO7 protein is an F-box-containing protein. Recessive FBXO7 mutations are responsible for PARK15, a rare juvenile parkinsonism characterized by progressive neurodegeneration with extrapyramidal and pyramidal system involvement. Our aim was to evaluate apoptosis in cells from two KRS siblings carrying a homozygous ATP13A2 mutation and a heterozygous FBXO7 mutation. We also analysed apoptosis in the patients' healthy parents. Peripheral blood lymphocytes from the KRS patients and parents were exposed to 2-deoxy-D-ribose; apoptosis was analysed by flow cytometry and fluorescence microscopy. Apoptosis was much higher in lymphocytes from the KRS patients and parents than in controls, both in standard conditions and after induction with a pro-apoptotic stimulus. The lack of correlation between increased apoptosis and the presence of the mutated FBXO7 gene rules out the involvement of FBXO7 in apoptosis regulation. The altered apoptotic pattern of subjects with mutated ATP13A2 suggests a correlation between apoptosis alteration and the mutated ATP13A2 protein. We hypothesize that ATP13A2 mutations may compromise protein function, disrupting cell cation balance and rendering cells prone to apoptosis. However, the deregulation of apoptosis in KRS patients displaying different disease severity suggested that the altered apoptotic pathway probably does not have a pathogenetic role in KRS by itself.
authors: Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Siena, Italy.
authors: Elena
authors: E
authors: Radi
authors: Patrizia
authors: P
authors: Formichi
authors: Giuseppe
authors: G
authors: Di Maio
authors: Carla
authors: C
authors: Battisti
authors: Antonio
authors: A
authors: Federico
mesh_terms: D000328:Adult; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D005089:Exocytosis; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D006180:Proton-Translocating ATPases / Q000235:genetics*; D035781:Siblings; D013194:Staining and Labeling
chemical_list: C514983:ATP13A2 protein, human; D017304:Annexin A5; D020169:Caspases; D006180:Proton-Translocating ATPases