Details

Autor(en) / Beteiligte

• Jepson, James E.C.
• Praschberger, Roman
• Krishnakumar, Shyam S.

Titel

Mechanisms of Neurological Dysfunction in GOSR2 Progressive Myoclonus Epilepsy, a Golgi SNAREopathy

Ist Teil von

• Neuroscience, 2019-11, Vol.420, p.41-49

Ort / Verlag

United States: Elsevier Ltd

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• Successive fusion events between transport vesicles and their target membranes mediate trafficking of secreted, membrane- and organelle-localised proteins. During the initial steps of this process, termed the secretory pathway, COPII vesicles bud from the endoplasmic reticulum (ER) and fuse with the cis-Golgi membrane, thus depositing their cargo. This fusion step is driven by a quartet of SNARE proteins that includes the cis-Golgi t-SNARE Membrin, encoded by the GOSR2 gene. Mis-sense mutations in GOSR2 result in Progressive Myoclonus Epilepsy (PME), a severe neurological disorder characterised by ataxia, myoclonus and seizures in the absence of significant cognitive impairment. However, given the ubiquitous and essential function of ER-to-Golgi transport, why GOSR2 mutations cause neurological dysfunction and not lethality or a broader range of developmental defects has remained an enigma. Here we highlight new work that has shed light on this issue and incorporate insights into canonical and non-canonical secretory trafficking pathways in neurons to speculate as to the cellular and molecular mechanisms underlying GOSR2 PME. This article is part of a Special Issue entitled: SNARE proteins: a long journey of science in brain physiology and pathology: from molecular. •Mutations in the Golgi t-SNARE GOSR2/Membrin cause progressive myoclonus epilepsy.•In this review, we summarise the functional effects of GOSR2 mutations on Membrin function and secretory trafficking.•We suggest potential mechanisms that may underlie the unique susceptibility of neurons to perturbations in the secretory pathway.•We present hypotheses that indicate which neuronal subclasses may be preferentially impacted by GOSR2 mutations.