Spastic Paraplegia and OXPHOS Impairment Caused by Mutations in Paraplegin, a Nuclear-Encoded Mitochondrial Metalloprotease

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.

Mitochondrial dynamics in the regulation of neuronal cell death

“…Interestingly, similar to Opa1, deficiency in Paraplegin causes a type of neuronal degenerative disease called hereditary spastic paraplegia (HSP). HSP causes degeneration of corticalspinal axons, one of the longest in neuronal system [98]. Some forms of HSP, similar to mutations of Opa1 in humans, can also lead to retinopathy and optic neuropathies [99].…”

Autocatalytic Processing of m-AAA Protease Subunits in Mitochondria

“…AAA proteases, conserved and membrane-bound ATP-dependent peptidases, are central for protein quality surveillance in the inner membrane . Mutations in subunits of these proteolytic complexes lead to axonal degeneration and neuronal cell death in human, illustrating their central role for mitochondrial integrity (Casari et al, 1998;Cagnoli et al, 2008;DiBella et al, 2008).…”

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

“…7 Mutations in the mitochondrial m-AAA proteases are responsible for neurodegenerative disorders including hereditary spastic paraplegia (HSP), spinocerebellar ataxia (SCA28) and spastic ataxia neuropathy syndrome. [8][9][10] However, the degenerative mechanisms remain elusive, 11 and the presence of multiple mitochondrial m-AAA proteases with redundant functions in eukaryotes complicates their analysis in animal models. By contrast, only one mitochondrial i-AAA protease has been identified in eukaryotic genomes.…”