title: A hereditary spastic paraplegia mouse model supports a role of ZFYVE26/SPASTIZIN for the endolysosomal system.
abstract: Hereditary spastic paraplegias (HSPs) are characterized by progressive weakness and spasticity of the legs because of the degeneration of cortical motoneuron axons. SPG15 is a recessively inherited HSP variant caused by mutations in the ZFYVE26 gene and is additionally characterized by cerebellar ataxia, mental decline, and progressive thinning of the corpus callosum. ZFYVE26 encodes the FYVE domain-containing protein ZFYVE26/SPASTIZIN, which has been suggested to be associated with the newly discovered adaptor protein 5 (AP5) complex. We show that Zfyve26 is broadly expressed in neurons, associates with intracellular vesicles immunopositive for the early endosomal marker EEA1, and co-fractionates with a component of the AP5 complex. As the function of ZFYVE26 in neurons was largely unknown, we disrupted Zfyve26 in mice. Zfyve26 knockout mice do not show developmental defects but develop late-onset spastic paraplegia with cerebellar ataxia confirming that SPG15 is caused by ZFYVE26 deficiency. The morphological analysis reveals axon degeneration and progressive loss of both cortical motoneurons and Purkinje cells in the cerebellum. Importantly, neuron loss is preceded by accumulation of large intraneuronal deposits of membrane-surrounded material, which co-stains with the lysosomal marker Lamp1. A density gradient analysis of brain lysates shows an increase of Lamp1-positive membrane compartments with higher densities in Zfyve26 knockout mice. Increased levels of lysosomal enzymes in brains of aged knockout mice further support an alteration of the lysosomal compartment upon disruption of Zfyve26. We propose that SPG15 is caused by an endolysosomal membrane trafficking defect, which results in endolysosomal dysfunction. This appears to be particularly relevant in neurons with highly specialized neurites such as cortical motoneurons and Purkinje cells.
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Mukhran
authors.initials: M
authors.lastname: Khundadze
authors.affiliation: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kollmann
authors.affiliation: Institute of Biochemistry I, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Koch
authors.affiliation: Department of Biomolecular Photonics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Biskup
authors.affiliation: Electron Microscopy Center, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Sandor
authors.initials: S
authors.lastname: Nietzsche
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Zimmer
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Hennings
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Antje K
authors.initials: AK
authors.lastname: Huebner
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Judit
authors.initials: J
authors.lastname: Symmank
authors.affiliation: Institute of Clinical Chemistry, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Amir
authors.initials: A
authors.lastname: Jahic
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Elena I
authors.initials: EI
authors.lastname: Ilina
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany ; German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Karle
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany ; German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: Institute of Biochemistry I, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kessels
authors.affiliation: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
authors.affiliation: Institute of Biochemistry I, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Qualmann
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
authors.affiliation: Institute of Clinical Chemistry, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Beetz
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003337:Corpus Callosum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D011992:Endosomes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; C528699:ZFYVE26 protein, human