A spastic paraplegia mouse model reveals REEP1-dependent ER shaping

Beetz, Christian; Koch, Nicole; Khundadze, Mukhran; Zimmer, Geraldine; Nietzsche, Sándor; Hertel, Nicole; Huebner, Antje-Kathrin; Mumtaz, Rizwan; Schweizer, Michaela; Dirren, Elisabeth; Karle, Kathrin N.; Irintchev, Andrey; Álvarez, Victoria; Redies, Christoph; Westermann, Martin; Kurth, Ingo; Deufel, Thomas; Kessels, Michael M.; Qualmann, Britta; Hübner, Christian A.

doi:10.1172/jci65665

Cited by 76 publications

(85 citation statements)

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“…Corresponding with the progressive gait disorder, we observed a degeneration of axons within the corticospinal tract at 8 months of age, a finding in line with mouse models of other types of HSP [20]–[22]. This degeneration mainly affected large diameter axons of the lumbar corticospinal tract.…”

Section: Discussionsupporting

confidence: 85%

A Hereditary Spastic Paraplegia Mouse Model Supports a Role of ZFYVE26/SPASTIZIN for the Endolysosomal System

et al. 2013

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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.

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Section: Discussionsupporting

confidence: 85%

A Hereditary Spastic Paraplegia Mouse Model Supports a Role of ZFYVE26/SPASTIZIN for the Endolysosomal System

et al. 2013

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“…Recently, a REEP1 gene knockout mouse model of HSP was created (Beetz et al, 2013). In situ hybridization analysis of an E18.5 murine sagittal embryo section demonstrated that REEP1 mRNA was only found in neuronal tissues, including cortical brain structures, brainstem, cerebellum, spinal cord, several major ganglia (e.g.…”

Section: Discussionmentioning

confidence: 99%

REEP1 and REEP2 proteins are preferentially expressed in neuronal and neuronal-like exocytotic tissues

Hurt

Björk

et al. 2014

Brain Research

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The six members of the Receptor Expression Enhancing Protein (REEP) family were originally identified based on their ability to enhance heterologous expression of olfactory receptors and other difficult to express G protein-coupled receptors. Interestingly, REEP1 mutations have been linked to neurodegenerative disorders of upper and lower motor neurons, hereditary spastic paraplegia (HSP) and distal hereditary motor neuropathy type V (dHMN-V). The closely related REEP2 isoform has not demonstrated any such disease linkage. Previous research has suggested that REEP1 mRNA is ubiquitously expressed in brain, muscle, endocrine, and multiple other organs, inconsistent with the neurodegenerative phenotype observed in HSP and dHMN-V. To more fully examine REEP1 expression, we developed and characterized a new REEP1 monoclonal antibody for both immunoblotting and immunofluorescent microscopic analysis. Unlike previous RT-PCR studies, immunoblotting demonstrated that REEP1 protein was not ubiquitous; its expression was restricted to neuronal tissues (brain, spinal cord) and testes. Gene expression microarray analysis demonstrated REEP1 and REEP2 mRNA expression in superior cervical and stellate sympathetic ganglia tissue. Furthermore, expression of endogenous REEP1 was confirmed in cultured murine sympathetic ganglion neurons by RTPCR and immunofluorescent staining, with expression occurring between Day 4 and Day 8 of culture. Lastly, we demonstrated that REEP2 protein expression was also restricted to neuronal tissues (brain and spinal cord) and tissues that exhibit neuronal-like exocytosis (testes, pituitary, and adrenal gland). In addition to sensory tissues, expression of the REEP1/REEP2 subfamily appears to be restricted to neuronal and neuronal-like exocytotic tissues, consistent with neuronally restricted symptoms of REEP1 genetic disorders.

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“…A mouse model of REEP1 deletion and a Drosophila model of Rtn2 deletion exhibit characteristics of HSP [77,80]. In general, neurons contain long protrusions, and the integrity of the ER network is more vulnerable to functional impairment.…”

Section: Er Morphology In Multicellular Developmentmentioning

confidence: 99%

Shaping the Endoplasmic Reticulum into a Social Network

Zhang

2016

Trends in Cell Biology

106

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In eukaryotic cells, the endoplasmic reticulum (ER) is constructed as a network of tubules and sheets that exist in one continuous membrane system. Several classes of integral membrane protein have been shown to shape ER membranes. Functional studies using mutant proteins have begun to reveal the significance of ER morphology and membrane dynamics. In this review, we discuss the common protein modules and mechanisms that generate the characteristic shape of the ER. We also describe the cellular functions closely related to ER morphology, particularly contacts with other membrane systems, and their potential roles in the development of multicellular organisms.

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A spastic paraplegia mouse model reveals REEP1-dependent ER shaping

Cited by 76 publications

References 50 publications

A Hereditary Spastic Paraplegia Mouse Model Supports a Role of ZFYVE26/SPASTIZIN for the Endolysosomal System

A Hereditary Spastic Paraplegia Mouse Model Supports a Role of ZFYVE26/SPASTIZIN for the Endolysosomal System

REEP1 and REEP2 proteins are preferentially expressed in neuronal and neuronal-like exocytotic tissues

Shaping the Endoplasmic Reticulum into a Social Network

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