title: A tail-anchored myotonic dystrophy protein kinase isoform induces perinuclear clustering of mitochondria, autophagy, and apoptosis.
abstract: BACKGROUND
  Studies on the myotonic dystrophy protein kinase (DMPK) gene and gene products have thus far mainly concentrated on the fate of length mutation in the (CTG)n repeat at the DNA level and consequences of repeat expansion at the RNA level in DM1 patients and disease models. Surprisingly little is known about the function of DMPK protein products.
  
  
  RESULTS
  We demonstrate here that transient expression of one major protein product of the human gene, the hDMPK A isoform with a long tail anchor, results in mitochondrial fragmentation and clustering in the perinuclear region. Clustering occurred in a variety of cell types and was enhanced by an intact tubulin cytoskeleton. In addition to morphomechanical changes, hDMPK A expression induces physiological changes like loss of mitochondrial membrane potential, increased autophagy activity, and leakage of cytochrome c from the mitochondrial intermembrane space accompanied by apoptosis. Truncation analysis using YFP-hDMPK A fusion constructs revealed that the protein's tail domain was necessary and sufficient to evoke mitochondrial clustering behavior.
  
  
  CONCLUSIONS
  Our data suggest that the expression level of the DMPK A isoform needs to be tightly controlled in cells where the hDMPK gene is expressed. We speculate that aberrant splice isoform expression might be a codetermining factor in manifestation of specific DM1 features in patients.
authors: Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Ralph J A
authors: RJ
authors: Oude Ophuis
authors: Mietske
authors: M
authors: Wijers
authors: Miranda B
authors: MB
authors: Bennink
authors: Fons A J
authors: FA
authors: van de Loo
authors: Jack A M
authors: JA
authors: Fransen
authors: Bé
authors: B
authors: Wieringa
authors: Derick G
authors: DG
authors: Wansink
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001426:Bacterial Proteins / Q000737:chemistry; D045304:Cytochromes c / Q000378:metabolism; D004247:DNA / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008164:Luminescent Proteins / Q000737:chemistry; D008564:Membrane Potentials; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D009154:Mutation; D065636:Myotonin-Protein Kinase; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*; D017434:Protein Structure, Tertiary
chemical_list: D001426:Bacterial Proteins; C585517:DMPK protein, human; C585516:DMPK protein, mouse; D008164:Luminescent Proteins; D020033:Protein Isoforms; C054562:yellow fluorescent protein, Bacteria; D045304:Cytochromes c; D004247:DNA; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases