The endosomal protein sorting nexin 4 is a synaptic protein

Sonia Vazquez-Sanchez; Miguel A. Gonzalez-Lozano; Alexarae Walfenzao; Ka Wan Li; Jan R.T. van Weering

doi:10.1038/s41598-020-74694-6

The endosomal protein sorting nexin 4 is a synaptic protein

Sonia Vazquez-Sanchez
, Miguel A. Gonzalez-Lozano
, Alexarae Walfenzao
, Ka Wan Li
, Jan R.T. van Weering^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Sorting nexin 4 (SNX4) is an evolutionary conserved protein that mediates recycling from endosomes back to the plasma membrane in yeast and mammalian cells. SNX4 is expressed in the brain. Altered protein levels are associated with Alzheimer’s disease, but the neuronal localization and function of SNX4 have not been addressed. Using a new antibody, endogenous neuronal SNX4 co-localized with both early and recycling endosome markers, similar to the reported localization of SNX4 in non-neuronal cells. Neuronal SNX4 accumulated specifically in synaptic areas, with a predominant localization to presynaptic terminals. Acute depletion of neuronal SNX4 using independent short hairpin RNAs did not affect the levels of the transferrin receptor, a canonical SNX4 cargo. Quantitative mass spectrometry revealed that upon SNX4 knockdown the class of proteins involved in neurotransmission was the most dysregulated. This included integral membrane proteins at both the presynaptic and postsynaptic side of the synapse that participate in diverse synaptic processes such as synapse assembly, neurotransmission and the synaptic vesicle cycle. These data suggest that SNX4 is implicated in a variety of synaptic processes.

Original language	English
Article number	18239
Pages (from-to)	1-12
Number of pages	12
Journal	Scientific Reports
Volume	10
DOIs	https://doi.org/10.1038/s41598-020-74694-6
Publication status	Published - 26 Oct 2020

Funding

The authors thank Prof. Dr. Matthijs Verhage and Prof. Dr. Peter J. Cullen, Dr Vera Wiersma and Mirjam Meu-lenbeld for their critical reading of the manuscript, Joke Wortel for housing and breeding the mice, Frank den Oudsten and Desiree Schut for providing cell cultures, Robbert Zalm and Joost Hoetjes for cloning and lentiviral production, Rozemarijn Jongeneel for confocal analysis and Joke Wortel and Marien P. Dekker for assistance with EM analysis. EM analysis was performed at the VU/VUmc EM facility (ZonMW 91111009). This work was supported by the EC under FP7-PEOPLE-2013 (607508), Alzheimer Nederland (WE.03-2016-05) and the Alzheimer Association (AARG-17-498856).

Funders	Funder number
Alzheimer Nederland
Alzheimer's Association	Alzheimer Association, AARG-17-498856
FP7-PEOPLE-2013	WE.03-2016-05
European Commission	607508

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 12 Responsible Consumption and Production

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10.1038/s41598-020-74694-6

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title = "The endosomal protein sorting nexin 4 is a synaptic protein",

abstract = "Sorting nexin 4 (SNX4) is an evolutionary conserved protein that mediates recycling from endosomes back to the plasma membrane in yeast and mammalian cells. SNX4 is expressed in the brain. Altered protein levels are associated with Alzheimer{\textquoteright}s disease, but the neuronal localization and function of SNX4 have not been addressed. Using a new antibody, endogenous neuronal SNX4 co-localized with both early and recycling endosome markers, similar to the reported localization of SNX4 in non-neuronal cells. Neuronal SNX4 accumulated specifically in synaptic areas, with a predominant localization to presynaptic terminals. Acute depletion of neuronal SNX4 using independent short hairpin RNAs did not affect the levels of the transferrin receptor, a canonical SNX4 cargo. Quantitative mass spectrometry revealed that upon SNX4 knockdown the class of proteins involved in neurotransmission was the most dysregulated. This included integral membrane proteins at both the presynaptic and postsynaptic side of the synapse that participate in diverse synaptic processes such as synapse assembly, neurotransmission and the synaptic vesicle cycle. These data suggest that SNX4 is implicated in a variety of synaptic processes.",

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AU - Gonzalez-Lozano, Miguel A.

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AU - Li, Ka Wan

AU - van Weering, Jan R.T.

PY - 2020/10/26

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N2 - Sorting nexin 4 (SNX4) is an evolutionary conserved protein that mediates recycling from endosomes back to the plasma membrane in yeast and mammalian cells. SNX4 is expressed in the brain. Altered protein levels are associated with Alzheimer’s disease, but the neuronal localization and function of SNX4 have not been addressed. Using a new antibody, endogenous neuronal SNX4 co-localized with both early and recycling endosome markers, similar to the reported localization of SNX4 in non-neuronal cells. Neuronal SNX4 accumulated specifically in synaptic areas, with a predominant localization to presynaptic terminals. Acute depletion of neuronal SNX4 using independent short hairpin RNAs did not affect the levels of the transferrin receptor, a canonical SNX4 cargo. Quantitative mass spectrometry revealed that upon SNX4 knockdown the class of proteins involved in neurotransmission was the most dysregulated. This included integral membrane proteins at both the presynaptic and postsynaptic side of the synapse that participate in diverse synaptic processes such as synapse assembly, neurotransmission and the synaptic vesicle cycle. These data suggest that SNX4 is implicated in a variety of synaptic processes.

AB - Sorting nexin 4 (SNX4) is an evolutionary conserved protein that mediates recycling from endosomes back to the plasma membrane in yeast and mammalian cells. SNX4 is expressed in the brain. Altered protein levels are associated with Alzheimer’s disease, but the neuronal localization and function of SNX4 have not been addressed. Using a new antibody, endogenous neuronal SNX4 co-localized with both early and recycling endosome markers, similar to the reported localization of SNX4 in non-neuronal cells. Neuronal SNX4 accumulated specifically in synaptic areas, with a predominant localization to presynaptic terminals. Acute depletion of neuronal SNX4 using independent short hairpin RNAs did not affect the levels of the transferrin receptor, a canonical SNX4 cargo. Quantitative mass spectrometry revealed that upon SNX4 knockdown the class of proteins involved in neurotransmission was the most dysregulated. This included integral membrane proteins at both the presynaptic and postsynaptic side of the synapse that participate in diverse synaptic processes such as synapse assembly, neurotransmission and the synaptic vesicle cycle. These data suggest that SNX4 is implicated in a variety of synaptic processes.

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The endosomal protein sorting nexin 4 is a synaptic protein

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