Study identifies elusive master regulator of synaptic protein sorting.


Synapses are specialized, protein-rich cell junctions that are essential for normal brain function and are dysfunctional in many diseases and disorders of the nervous system. Synapses are made up of many different proteins that link neurons together and regulate communication between these cells.   At early stages of differentiation neurons already contain many of the components necessary for synaptic transmission.  At the presynaptic level, synaptic vesicles (SVs) must acquire the highly specialized complement of proteins, which make them competent for efficient neurotransmitter release.

Although several of these proteins have been characterized and linked to precise functions in the regulation of the SV life cycle, a systematic and unifying view of the mechanisms underlying selective protein sorting during SV biogenesis remains elusive.  Now, a new study in rats from researchers at Northwestern University and VIB/KU Leuven has revealed for the first time a new pathway that governs the proper sorting of many essential synaptic proteins in neurons. The team state that disruption of this sorting pathway in neuropsychiatric and neurological diseases severely hampers the efficient communication between neurons.  The opensource study is published in the journal Neuron.

Previous genetic analysis of human patients has shown that mutations in genes involved in synaptic communication can drive neuropsychiatric and neurological diseases such as autism spectrum disorder and Alzheimer’s disease.  The proper formation and function of synapses require the coordinated assembly of large and heterogeneous protein complexes on the pre- and postsynaptic side. The composition of the synaptic proteome varies with synaptic neurotransmitter type and developmental stage with earlier studies showing many different protein sorting pathways involved in synaptic and proper vesicle formation.

The current study used novel high-content protein analysis to study the entire synaptic machinery on a genomic level as opposed to individual parts and proteins. The results identified a master regulator of sorting of synaptic proteins and showed that experimental disruption of this pathway impedes efficient communication between neurons.

The lab state that the name of this master of synaptic receptor trafficking is the sorting receptor SorCS1.  Data findings observed that SorCS1 knockout synaptic proteomes had decreased levels of receptors regulating adhesion and neurotransmission, including neurexins and AMPARs.  The researchers note that SORCS1 mutations have been associated with autism and Alzheimer’s disease, suggesting that perturbed receptor trafficking contributes to synaptic-composition and function defects.

The team surmise that their study highlights the importance of proper synaptic protein sorting for efficient neuronal communication and suggests that therapeutic targeting of this pathway could prove beneficial to improve synaptic function in brain disorders.  The researchers conclude that perturbed sorting of these synaptic proteins hampers neuron-neuron communication and culminates in an increased level of silent synapses.

For the future the team hypothesize that therapeutic targeting of this master regulator pathway may prove efficacious in treating multiple neurological diseases.

Source:  VIB/KU Leuven

SorCS1 localizes to endosomal compartments and excitatory synapses. (H) HA-SorCS1cb (green) coexpressed with GFP (blue) colocalizes with EEA1 (red) in dendrites and spines of hippocampal neurons (arrows). (I) HA-SorCS1cb colocalizes with Alexa 568-Tf (red) in dendrites and spines (arrows). (J) SorCS1cb-myc shows a partial overlap with postsynaptic excitatory marker PSD95 (red) in dendritic spines (arrows). The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors. Yates et al 2015.

SorCS1 localizes to endosomal compartments and excitatory synapses. (H) HA-SorCS1cb (green) coexpressed with GFP (blue) colocalizes with EEA1 (red) in dendrites and spines of hippocampal neurons (arrows). (I) HA-SorCS1cb colocalizes with Alexa 568-Tf (red) in dendrites and spines (arrows).
(J) SorCS1cb-myc shows a partial overlap with postsynaptic excitatory marker PSD95 (red) in dendritic spines (arrows). The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors. Yates et al 2015.

 

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