At the level of the whole protein expression profile, populations from similar climates tended very strongly to be more similar to one another

ract Hereditary spastic paraplegias 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 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. Citation: Joshi DC, Bakowska JC SPG20 Protein Spartin Associates with Cardiolipin via Its Plant-Related Senescence Domain and Regulates Mitochondrial Ca2+ Homeostasis. PLoS ONE 6: e19290. doi:10.1371/journal.pone.0019290 Editor: Mark R. Cookson, National Institutes of Health, United States of America Received November 21, 2010; Accepted April 1, 2011; Published April 29, 2011 McMMAF Copyright: 2011 Joshi, Bakowska. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. E-mail: [email protected] Introduction The hereditary spastic paraplegias are inherited neurological disorders characterized by a common feature of progressive spasticity in the lower limbs with degeneration of corticospinal projections of motor neurons. Troyer syndrome is an autosomal recessive HSP, in which patients show spasticity of lower limbs as well as other symptoms, including mental retardation, dysarthria, and short stature. The disease is caused by a frameshift mutation in the spartin gene resulting in a lack of expression of spartin rather than expression of a truncated protein, indicating that the pathogenesis of Troyer syndrome results from a loss-of-function mechanism. Spartin harbors two conserved domains, an MIT domain at the N-terminus and a plant-related senescence domain at the C-terminus. Currently, neither the function nor the binding partners of the plant-related senescence domain are known. The following evidence suggests that the spartin protein plays diverse roles in the biology the cell: the presence of different structural domains within spartin, its associati

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