Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11

Authors

  • Benoît Renvoisé,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
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    • These authors contributed equally to this work
  • Jaerak Chang,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
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    • These authors contributed equally to this work
  • Rajat Singh,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
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  • Sayuri Yonekawa,

    1. Research Institute, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
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  • Edmond J. FitzGibbon,

    1. Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland
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  • Ami Mankodi,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
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  • Adeline Vanderver,

    1. Department of Neurology, Children's National Medical Center, Washington, District of Columbia
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  • Alice B. Schindler,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
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  • Camilo Toro,

    1. Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
    2. NIH Undiagnosed Diseases Program, National Institutes of Health, Office of Rare Diseases Research and National Human Genome Research Institute, Bethesda, Maryland
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  • William A. Gahl,

    1. Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
    2. NIH Undiagnosed Diseases Program, National Institutes of Health, Office of Rare Diseases Research and National Human Genome Research Institute, Bethesda, Maryland
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  • Don J. Mahuran,

    1. Research Institute, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
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  • Craig Blackstone,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
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  • Tyler Mark Pierson

    Corresponding author
    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
    2. NIH Undiagnosed Diseases Program, National Institutes of Health, Office of Rare Diseases Research and National Human Genome Research Institute, Bethesda, Maryland
    3. Departments of Pediatrics and Neurology, and the Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • Correspondence

      Tyler Mark Pierson, Departments of Pediatrics and Neurology, and the Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, ASHP 8401, Los Angeles, CA 90048. Tel: 310-248-8558; Fax: 310-248-8066; E-mail: tyler.pierson@cshs.org

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Abstract

Objective

Hereditary spastic paraplegias (HSPs) are among the most genetically diverse inherited neurological disorders, with over 70 disease loci identified (SPG1-71) to date. SPG15 and SPG11 are clinically similar, autosomal recessive disorders characterized by progressive spastic paraplegia along with thin corpus callosum, white matter abnormalities, cognitive impairment, and ophthalmologic abnormalities. Furthermore, both have been linked to early-onset parkinsonism.

Methods

We describe two new cases of SPG15 and investigate cellular changes in SPG15 and SPG11 patient-derived fibroblasts, seeking to identify shared pathogenic themes. Cells were evaluated for any abnormalities in cell division, DNA repair, endoplasmic reticulum, endosomes, and lysosomes.

Results

Fibroblasts prepared from patients with SPG15 have selective enlargement of LAMP1-positive structures, and they consistently exhibited abnormal lysosomal storage by electron microscopy. A similar enlargement of LAMP1-positive structures was also observed in cells from multiple SPG11 patients, though prominent abnormal lysosomal storage was not evident. The stabilities of the SPG15 protein spastizin/ZFYVE26 and the SPG11 protein spatacsin were interdependent.

Interpretation

Emerging studies implicating these two proteins in interactions with the late endosomal/lysosomal adaptor protein complex AP-5 are consistent with shared abnormalities in lysosomes, supporting a converging mechanism for these two disorders. Recent work with Zfyve26−/− mice revealed a similar phenotype to human SPG15, and cells in these mice had endolysosomal abnormalities. SPG15 and SPG11 are particularly notable among HSPs because they can also present with juvenile parkinsonism, and this lysosomal trafficking or storage defect may be relevant for other forms of parkinsonism associated with lysosomal dysfunction.

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