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Publication - Dr Maria Usowicz

    Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity

    Citation

    Praschberger, R, Lowe, SA, Malintan, NT, Giachello, CNG, Patel, N, Houlden, H, Kullmann, DM, Baines, RA, Usowicz, MM, Krishnakumar, SS, Hodge, JJL, Rothman, JE & Jepson, JEC, 2017, ‘Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity’. Cell Reports, vol 21., pp. 97-109

    Abstract

    Mutations in the Golgi SNARE 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 trans-synaptic instability and hyperactive neurotransmission. Our study highlights how dendritic growth is vulnerable even to subtle secretory pathway deficits, uncovers a previously uncharacterized role for Membrin in synaptic function, and provides a comprehensive explanatory basis for genotype-phenotype relationships in GOSR2-PME.

    Full details in the University publications repository