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Mitochondrial protein alterations in a familial peripheral neuropathy caused by the V144D amino acid mutation in the sphingolipid protein, SPTLC1

  • Original Article
  • Published:
Journal of Chemical Biology

Abstract

Axonal degeneration is the final common path in many neurological disorders. Subsets of neuropathies involving the sensory neuron are known as hereditary sensory neuropathies (HSNs). Hereditary sensory neuropathy type I (HSN-I) is the most common subtype of HSN with autosomal dominant inheritance. It is characterized by the progressive degeneration of the dorsal root ganglion (DRG) with clinical symptom onset between the second or third decade of life. Heterozygous mutations in the serine palmitoyltransferase (SPT) long chain subunit 1 (SPTLC1) gene were identified as the pathogenic cause of HSN-I. Ultrastructural analysis of mitochondria from HSN-I patient cells has displayed unique morphological abnormalities that are clustered to the perinucleus where they are wrapped by the endoplasmic reticulum (ER). This investigation defines a small subset of proteins with major alterations in abundance in mitochondria harvested from HSN-I mutant SPTLC1 cells. Using mitochondrial protein isolates from control and patient lymphoblasts, and a combination of 2D gel electrophoresis, immunoblotting and mass spectrometry, we have shown the increased abundance of ubiquinol-cytochrome c reductase core protein 1, an electron transport chain protein, as well as the immunoglobulin, Ig kappa chain C. The regulation of these proteins may provide a new route to understanding the cellular and molecular mechanisms underlying HSN-I.

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Acknowledgments

We are grateful to Prof. Garth Nicholson (Molecular Medicine Laboratory and Northcott Neuroscience Laboratory Anzac Research Institute, Sydney) for providing all EBV-transformed lymphoblast lines used in this study. SES was supported by APA Research Scholarship and the UWS School of Science and Health Postgraduate research fund. SJM notes the continuing support of an anonymous private foundation. JRC acknowledges the support of the UWS School of Medicine.

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Authors and Affiliations

  1. Neuro-Cell Biology Laboratory, University of Western Sydney, Penrith, Australia

    Scott E. Stimpson & Simon J. Myers

  2. Molecular Physiology, University of Western Sydney, Penrith, Australia

    Jens R. Coorssen

  3. Molecular Medicine Research Group, University of Western Sydney, Penrith, Australia

    Scott E. Stimpson, Jens R. Coorssen & Simon J. Myers

  4. School of Science and Health, University of Western Sydney, Penrith, Australia

    Scott E. Stimpson, Jens R. Coorssen & Simon J. Myers

  5. School of Medicine, University of Western Sydney, Locked Bag 1797, Penrith, NSW, 2751, Australia

    Jens R. Coorssen & Simon J. Myers

  6. University of Western Sydney, Office 21.1.05, Campbelltown campus, Locked Bag 1797, Penrith, NSW, 2751, Australia

    Simon J. Myers

  7. School of Medicine, University of Western Sydney, Office 30.2.15, Campbelltown campus, Locked Bag 1797, Penrith, NSW, 2751, Australia

    Jens R. Coorssen

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  1. Scott E. Stimpson
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Correspondence to Jens R. Coorssen or Simon J. Myers.

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Stimpson, S.E., Coorssen, J.R. & Myers, S.J. Mitochondrial protein alterations in a familial peripheral neuropathy caused by the V144D amino acid mutation in the sphingolipid protein, SPTLC1. J Chem Biol 8, 25–35 (2015). https://doi.org/10.1007/s12154-014-0125-x

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  • DOI: https://doi.org/10.1007/s12154-014-0125-x

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