A hereditary spastic paraplegia mouse model supports a role of ZFYVE26/SPASTIZIN for the endolysosomal system

PLoS Genet. 2013;9(12):e1003988. doi: 10.1371/journal.pgen.1003988. Epub 2013 Dec 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Corpus Callosum / metabolism
  • Corpus Callosum / pathology
  • Disease Models, Animal
  • Endosomes / metabolism*
  • Endosomes / pathology
  • Humans
  • Lysosomes / genetics
  • Lysosomes / metabolism*
  • Mice
  • Mice, Knockout
  • Motor Neurons / metabolism
  • Mutation
  • Retinal Degeneration / genetics*
  • Retinal Degeneration / metabolism
  • Retinal Degeneration / pathology
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / metabolism
  • Spastic Paraplegia, Hereditary / pathology


  • Carrier Proteins
  • ZFYVE26 protein, human

Supplementary concepts

  • Spastic paraplegia 15, autosomal recessive

Grants and funding

The study was supported by grants of the DFG DE 807/8-1 (CAH), QU116/5-2 (BQ), KE685/3-1 (MKe), the IZKF Jena, and the Thyssenfoundation to CAH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.