alternative splicing of spg7, a gene involved in hereditary spastic paraplegia, encodes a variant of paraplegin targeted to the endoplasmic reticulumspg7的可变剪接基因参与遗传性痉挛性截瘫,编码paraplegin针对内质网的一个变体.pdfVIP

Alternative Splicing of Spg7, a Gene Involved in Hereditary Spastic Paraplegia, Encodes a Variant of Paraplegin Targeted to the Endoplasmic Reticulum 1 1 2¤ 1,3,4 Giuseppe Mancuso , Esther Barth , Pietro Crivello , Elena I. Rugarli * ¨ 1 Institute of Zoology, University of Cologne, Koln, Germany, 2 National Neurological Institute Carlo Besta, Milan, Italy, 3 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany, 4 Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany 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. Principal Findings: 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 frac