SPG20 protein spartin associates with cardiolipin via its plant-related senescence domain and regulates mitochondrial Ca2+ homeostasis

Hereditary spastic paraplegias (HSPs) are a group of neurological disorders characterized clinically by spasticity of lower limbs and pathologically by degeneration of the corticospinal tract. Troyer syndrome is an autosomal recessive HSP caused by a frameshift mutation in the spartin (SPG20) gene....

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Bibliographic Details
Published in:PloS one 2011-04, Vol.6 (4), p.e19290
Main Authors: Joshi, Dinesh C, Bakowska, Joanna C
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Animals
Apoptosis
Axons
Axons - pathology
Bands
Biology
Biosynthesis
C-Terminus
Calcium
Calcium (mitochondrial)
Calcium - chemistry
Calcium homeostasis
Calcium influx
Cardiolipin
Cardiolipins - chemistry
Carrier Proteins - chemistry
Carrier Proteins - genetics
Cystic fibrosis
Degeneration
Depolarization
Endoplasmic reticulum
Fibroblasts
Frameshift mutation
Gene Deletion
Gene Expression Regulation
Homeostasis
Humans
Immunoglobulins
Lecithin
Localization
Medicine
Membrane potential
Mice
Mice, Knockout
Mitochondria
Mitochondria - metabolism
Mutation
Neurodegeneration
Neurological diseases
Neurons - pathology
Nitric oxide
Organelles
Oxidative stress
Pathogenesis
Phosphatidylcholine
Phosphatidylethanolamine
Phospholipids
Plants - metabolism
Protein Binding
Protein Structure, Tertiary
Proteins
Proteins - chemistry
Proteins - metabolism
Pyramidal tracts
Respiration
Ribonucleic acid
RNA
Senescence
siRNA
Spastic Paraplegia, Hereditary - physiopathology
Spasticity
Thapsigargin
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Summary:Hereditary spastic paraplegias (HSPs) are a group of neurological disorders characterized clinically by spasticity of lower limbs and pathologically by degeneration of the corticospinal tract. Troyer syndrome is an autosomal recessive HSP caused by a frameshift mutation in the spartin (SPG20) gene. Previously, we established that this mutation results in a lack of expression of the truncated mutant spartin protein. Spartin is involved in many cellular processes and associates with several intracellular organelles, including mitochondria. Spartin contains a conserved plant-related senescence domain at its C-terminus. However, neither the function of this domain nor the roles of spartin in mitochondrial physiology are currently known. In this study, we determined that the plant-related senescence domain of spartin interacts with cardiolipin but not with two other major mitochondrial phospholipids, phosphatidylcholine and phosphatidylethanolamine. We also found that knockdown of spartin by small interfering RNA in a human neuroblastoma cell line resulted in depolarization of the mitochondrial membrane. In addition, depletion of spartin resulted in a significant decrease in both mitochondrial calcium uptake and mitochondrial membrane potential in cells treated with thapsigargin. Our results suggest that impairment of mitochondrial calcium uptake might contribute to the neurodegeneration of long corticospinal axons and the pathophysiology of Troyer syndrome.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0019290