Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity
Roman Praschberger,
Simon A. Lowe,
Nancy T. Malintan,
Carlo N.G. Giachello,
Nian Patel,
Henry Houlden,
Dimitri M. Kullmann,
Richard A. Baines,
Maria M. Usowicz,
Shyam S. Krishnakumar,
James J.L. Hodge,
James E. Rothman,
James E.C. Jepson
Affiliations
Roman Praschberger
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Simon A. Lowe
School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, UK
Nancy T. Malintan
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Carlo N.G. Giachello
Faculty of Biology, Medicine, and Health, Division of Neuroscience & Experimental Psychology, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
Nian Patel
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Henry Houlden
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Dimitri M. Kullmann
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Richard A. Baines
Faculty of Biology, Medicine, and Health, Division of Neuroscience & Experimental Psychology, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
Maria M. Usowicz
School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, UK
Shyam S. Krishnakumar
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
James J.L. Hodge
School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, UK
James E. Rothman
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
James E.C. Jepson
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Mutations in the Golgi SNARE (SNAP [soluble NSF attachment protein] receptor) protein Membrin (encoded by the GOSR2 gene) cause progressive myoclonus epilepsy (PME). Membrin is a ubiquitous and essential protein mediating ER-to-Golgi membrane fusion. Thus, it is unclear how mutations in Membrin result in a disorder restricted to the nervous system. Here, we use a multi-layered strategy to elucidate the consequences of Membrin mutations from protein to neuron. We show that the pathogenic mutations cause partial reductions in SNARE-mediated membrane fusion. Importantly, these alterations were sufficient to profoundly impair dendritic growth in Drosophila models of GOSR2-PME. Furthermore, we show that Membrin mutations cause fragmentation of the presynaptic cytoskeleton coupled with transsynaptic instability and hyperactive neurotransmission. Our study highlights how dendritic growth is vulnerable even to subtle secretory pathway deficits, uncovers a role for Membrin in synaptic function, and provides a comprehensive explanatory basis for genotype-phenotype relationships in GOSR2-PME.
