Liprin-α proteins are master regulators of human presynapse assembly

Marco de La Cruz, Berta,1990Gothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine (author)

The formation of mammalian synapses entails the precise alignment of presynaptic release sites with postsynaptic receptors but how nascent cell-cell contacts translate into assembly of presynaptic specializations remains unclear. Guided by pioneering work in invertebrates, we hypothesized that in mammalian synapses, liprin-alpha proteins directly link trans-synaptic initial contacts to downstream steps. Here we show that, in human neurons lacking all four liprin-alpha isoforms, nascent synaptic contacts are formed but recruitment of active zone components and accumulation of synaptic vesicles is blocked, resulting in 'empty' boutons and loss of synaptic transmission. Interactions with presynaptic cell adhesion molecules of either the LAR-RPTP family or neurexins via CASK are required to localize liprin-alpha to nascent synaptic sites. Liprin-alpha subsequently recruits presynaptic components via a direct interaction with ELKS proteins. Thus, assembly of human presynaptic terminals is governed by a hierarchical sequence of events in which the recruitment of liprin-alpha proteins by presynaptic cell adhesion molecules is a critical initial step. This paper identifies the evolutionarily conserved liprin-alpha protein family as key mediators of presynaptic assembly in human neurons. Their recruitment to sites formed by contacting neurons is the critical initial step that triggers presynaptic differentiation.

Campos, Joaquin (author)
Molinaro, AngelaGothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine (author)
Xie, Xingqiao (author)
Jin, Gaowei (author)
Wei, Zhiyi (author)
Acuna, Claudio (author)
Sterky, Fredrik HGothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine(Swepub:gu)xsterf (author)
Göteborgs universitetWallenberg Centre for Molecular and Translational Medicine (creator_code:org_t)

By the author/editor: Marco de La Cruz ...; Campos, Joaquin; Molinaro, Angela; Xie, Xingqiao; Jin, Gaowei; Wei, Zhiyi; show more...; Acuna, Claudio; Sterky, Fredrik ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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