Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease

Giorgio Casari, Maurizio De Fusco, Sonia Ciarmatori, Massimo Zeviani, Marina Mora, Patricio Fernandez, Giuseppe De Michele, Alessandro Filla, Sergio Cocozza, Roberto Marconi, Alexandre Dürr, Bertrand Fontaine, Andrea Ballabio

Research output: Contribution to journalArticlepeer-review

Abstract

Hereditary spastic paraplegia (HSP) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. We found that patients from a chromosome 16q24.3-linked HSP family are homozygous for a 9.5 kb deletion involving a gene encoding a novel protein, named Paraplegin. Two additional Paraplegin mutations, both resulting in a frameshift, were found in a complicated and in a pure form of HSP. Paraplegin is highly homologous to the yeast mitochondrial ATPases, AFG3, RCA1, and YME1, which have both proteolytic and chaperon-like activities at the inner mitochondrial membrane. Immunofluorescence analysis and import experiments showed that Paraplegin localizes to mitochondria. Analysis of muscle biopsies from two patients carrying Paraplegin mutations showed typical signs of mitochondrial OXPHOS defects, thus suggesting a mechanism for neurodegeneration in HSP-type disorders.

Original languageEnglish
Pages (from-to)973-983
Number of pages11
JournalCell
Volume93
Issue number6
DOIs
Publication statusPublished - Jun 12 1998

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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