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.
Highlights
Hereditary spastic paraplegias (HSPs/SPGs) are a heterogeneous group of neurodegenerative movement disorders, which present with progressive weakness and spasticity of the legs
Hereditary spastic paraplegias (HSPs) are inherited disorders characterized by progressive weakness and spasticity of the legs
We show that the Zfyve26 protein is broadly expressed in the brain
Summary
Hereditary spastic paraplegias (HSPs/SPGs) are a heterogeneous group of neurodegenerative movement disorders, which present with progressive weakness and spasticity of the legs. The unifying neuropathology is a time- and length-dependent degeneration of cortical motoneuron axons. Whereas in pure HSP other cells of the central nervous system are usually spared, neurodegeneration in complex HSP is more widespread and results in additional clinical symptoms. The age at onset and the course of disease are highly variable [1,2,3]. The clinical variability is mirrored by more than 50 spastic paraplegia gene loci, characterizing HSP as a genetically highly heterogeneous disease. HSP is considered a model disease for unraveling the various requirements for long-term axon survival [4]
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