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Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease.

MPG-Autoren
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Binotti,  B.
Department of Neurobiology, MPI for Biophysical Chemistry, Max Planck Society;

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Perez-Lara,  A.
Department of Neurobiology, MPI for Biophysical Chemistry, Max Planck Society;

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Jahn,  R.
Department of Neurobiology, MPI for Biophysical Chemistry, Max Planck Society;

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Zitation

Lüningschrör, P., Binotti, B., Dombert, B., Heimann, P., Perez-Lara, A., Slotta, C., et al. (2017). Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease. Nature Communications, 8: 678. doi:10.1038/s41467-017-00689-z.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-002E-1DF9-E
Zusammenfassung
Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease.