title: Alternative splicing of Spg7, a gene involved in hereditary spastic paraplegia, encodes a variant of paraplegin targeted to the endoplasmic reticulum.
abstract: BACKGROUND
  Hereditary spastic paraplegia defines a group of genetically heterogeneous diseases characterized by weakness and spasticity of the lower limbs owing to retrograde degeneration of corticospinal axons. One autosomal recessive form of the disease is caused by mutation in the SPG7 gene. Paraplegin, the product of SPG7, is a component of the m-AAA protease, a high molecular weight complex that resides in the mitochondrial inner membrane, and performs crucial quality control and biogenesis functions in mitochondria.
  
  
  RESULTS
  Here we show the existence in the mouse of a novel isoform of paraplegin, which we name paraplegin-2, encoded by alternative splicing of Spg7 through usage of an alternative first exon. Paraplegin-2 lacks the mitochondrial targeting sequence, and is identical to the mature mitochondrial protein. Remarkably, paraplegin-2 is targeted to the endoplasmic reticulum. We find that paraplegin-2 exposes the catalytic domains to the lumen of the endoplasmic reticulum. Moreover, endogenous paraplegin-2 accumulates in microsomal fractions prepared from mouse brain and retina. Finally, we show that the previously generated mouse model of Spg7-linked hereditary spastic paraplegia is an isoform-specific knock-out, in which mitochondrial paraplegin is specifically ablated, while expression of paraplegin-2 is retained.
  
  
  CONCLUSIONS
  These data suggest a possible additional role of AAA proteases outside mitochondria and open the question of their implication in neurodegeneration.
authors.affiliation: Institute of Zoology, University of Cologne, Köln, Germany.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mancuso
authors.forename: Esther
authors.initials: E
authors.lastname: Barth
authors.forename: Pietro
authors.initials: P
authors.lastname: Crivello
authors.forename: Elena I
authors.initials: EI
authors.lastname: Rugarli
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics / Q000378:metabolism; D000074183:ATPases Associated with Diverse Cellular Activities; D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D020224:Expressed Sequence Tags; D006801:Humans; D006822:Hybrid Cells; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008861:Microsomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology; D009447:Neuroblastoma / Q000473:pathology; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D012160:Retina / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D049069:ATP-Dependent Proteases; C542395:Afg3l2 protein, mouse; D008666:Metalloendopeptidases; C491813:Spg7 protein, mouse; D000074183:ATPases Associated with Diverse Cellular Activities