Alternative splicing of Spg7, a gene involved in hereditary spastic paraplegia, encodes a variant of paraplegin targeted to the endoplasmic reticulum.

PloS One
Giuseppe MancusoElena I Rugarli

Abstract

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. 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 mitochondria...Continue Reading

References

Jul 1, 1992·Developmental Dynamics : an Official Publication of the American Association of Anatomists·N R CashmanJ P Antel
Dec 1, 1993·Seminars in Neurology·A E Harding
Jan 15, 2004·The Journal of Clinical Investigation·Fatima FerreirinhaElena I Rugarli
Feb 27, 2004·Brain : a Journal of Neurology·Philip A WilkinsonThomas T Warner
Dec 17, 2005·The Journal of Clinical Investigation·Marinella PirozziElena I Rugarli
Jun 17, 2006·The EMBO Journal·Naotada IshiharaKatsuyoshi Mihara
Apr 5, 2007·Nature Protocols·Holger LorenzJennifer Lippincott-Schwartz
Jun 15, 2007·Nature Reviews. Molecular Cell Biology·David Ron, Peter Walter
Jan 25, 2008·The EMBO Journal·Takashi Tatsuta, Thomas Langer
Jul 1, 2008·Neurobiology of Disease·Daisuke ItoNorihiro Suzuki
Sep 19, 2008·Neurology·F BrugmanL H van den Berg
Aug 7, 2009·Molecular Biology of the Cell·Mirko KoppenThomas Langer
Sep 15, 2009·Molecular Cell·Steffen AugustinTakashi Tatsuta
Dec 30, 2009·The Journal of Cell Biology·Sarah EhsesThomas Langer
Dec 9, 2010·Nature Reviews. Neuroscience·Craig BlackstoneEvan Reid
Apr 8, 2011·Annual Review of Biochemistry·Robert T Sauer, Tania A Baker

❮ Previous
Next ❯

Citations

Mar 11, 2015·Expert Review of Proteomics·Edward LauPeipei Ping
Dec 18, 2019·Movement Disorders : Official Journal of the Movement Disorder Society·Josef Finsterer

❮ Previous
Next ❯

Methods Mentioned

BETA
transfection
gel filtration

Software Mentioned

METAMORPH
Ensembl
UCSC browser
Mitoprot

Related Concepts

Related Feeds

Antisense Oligonucleotides: ND

This feed focuses on antisense oligonucleotide therapies such as Inotersen, Nusinursen, and Patisiran, in neurodegenerative diseases including amyotrophic lateral sclerosis.

Ataxias

Ataxia is a neurological condition characterized by lack of voluntary coordination of muscle movements including loss of coordination, balance, and speech. Discover the latest research on different types of ataxias here.

Alternative splicing

Alternative splicing a regulated gene expression process that allows a single genetic sequence to code for multiple proteins. Here is that latest research.