Menu

Close

Proteomic Studies reveal Disrupted in Schizophrenia 1 as a key regulator unifying neurodevelopment and synaptic function

Adriana Ramos, Carmen Rodriguez-Seoane, Isaac Rosa, Irantzu Gorrono-Etxebarria, Jana Alonso, Sonia Veiga, Carsten Korth, Robert M. Kypta, Angel Garcia, Jesus R. Requena

Preprint posted on November 19, 2018 https://www.preprints.org/manuscript/201811.0467/v1

One DISC to rule them all: DISC1 is a central regulator in a network of proteins involved in neurodevelopment and its disruption could segregate with risk of mental diseases

Selected by Yasmin Lau

Categories: neuroscience

Background:
The Disrupted in Schizophrenia 1 (DISC1) gene has gained increasing recognition as studies have revealed its significance in regulating a number of processes in synapse function and regulation. These findings stem from studies on a diverse range of pathways, including those on DISC1 chromosomal translocation, gene truncation and molecular studies on its binding partners. An example of the role of DISC1 as a molecular bridge in neuronal development is a study on components involved in regulation of neurogenesis in mice. The study highlights the interplay between intrinsic DISC1 and extrinsic GABA signaling which are pathways critical for regulating neurogenesis and influence risk of development of mental disorders such as schizophrenia (1). The revelation of chromosomal translocation underlying neurogenesis hindrance arises from another study by Millar et al, in which a balanced translocation of chromosome 1 in humans was found to cause disruption in gene function, and thus structural functionality, of DISC1 leading to psychosis (2).This further demonstrates the importance of the DISC1 gene in neural and synaptic function.
In this preprint, the authors have revealed the involvement of DISC1 in various mechanisms such as regulation of CRMP proteins in neuronal differentiation and axonal development (3), among many others. The discovery of such pathways which are dependent on DISC1 provides further useful insight to its role in the landscape of mental diseases and could drive the discernment of novel therapeutic targets.

Key Findings:
Firstly, a proteomic analysis was carried out on both wild-type and DISC1 knockout cells using 4 2D gel electrophoreses each, in which spots on each gel were compared. 48 proteins differentially expressed between the two cell types were identified with mass spectrometry, most of which have reported functions related to neurodevelopment and synaptic function. In particular, several proteins amongst these have also been reported to be binding partners of DISC1 such as 14-3-3 proteins and LIS1 (4) as well as CRMP-2, a potential DISC1 interactor. This is interesting as it could indicate that, in addition to binding, such proteins are also regulated by DISC1 (either over-expressed or down regulated) in pathways contributing to neurodevelopment.
Secondly, the Ingenuity Pathway Analysis software was used to verify common pathways shared amongst the proteins identified as seen in the table below.

Following the identification of common pathways, it was worthwhile to further scrutinize the CRMPs (collapsin response mediator proteins) in particular, as Semaphorin signaling is an integral component of axonal growth. Interestingly, the truncation of the DISC1 gene (leading to altered protein structure) was previously found to cause disruption of the Semaphorin pathway in neurons (5) which further implicates the potential of CRMP regulation by DISC1. All CRMPs were up-regulated in DISC1 silenced cells, and particularly 1 in 3 isoforms of CRMP-2 was up-regulated while the other 2 were down-regulated; this suggests that wild-type DISC1 could play a role in suppressing CRMP expression and thus appropriately regulating Semaphorin signaling.

Another key finding was the morphological changes of neurite growth exhibited in SH-SY5Y neuroblastoma cells with silenced DISC1. As SH-SY5Y cells are commonly used for the study of
neuronal differentiation and function, those with silenced DISC1 are useful for demonstrating whether DISC1 is involved in such pathways. Fluorescence microscopy images comparing control and DISC1-silenced cells showed significant growth impairments in the latter upon retinoic acid- induced differentiation as seen in the figure below. Frequency of cells by neurite length was also measured for control and silenced in which the latter showed around 20 and 50 micrometers shorter neurite at the 50 percentile at 7 and 14 days RA exposure respectively.

Why I chose this article:
The elucidation of the molecular mechanisms of mental illnesses is highly challenging, despite the prominence of patients suffering from such diseases as schizophrenia and depression. The findings in this preprint form a useful foundation for the development of new treatment strategies. DISC1 appears to be a molecular scaffold regulating various signaling pathways and many possibilities as drug targets are presented for further research.

Questions for the authors:
1. In addition to neurite length and synapse formation, what other morphological changes in SH-SY5Y (or other) cells could be used to probe impairment of neurodevelopment?
2. Considering the opposite expression patterns of the different 14-3-3 proteins in DISC1 knockdowns, what could be the molecular mechanism of DISC1 in binding and signaling of the 3 14-3-3 proteins causing such opposing results in the context of neurite growth?

References
1. Kim, J., Liu, C., Zhang, F., Duan, X., Wen, Z., Song, J., Feighery, E., Lu, B., Rujescu, D., St Clair, D., Christian, K., Callicott, J., Weinberger, D., Song, H. and Ming, G. (2012). Interplay between DISC1 and GABA Signaling Regulates Neurogenesis in Mice and Risk for Schizophrenia. Cell, 148(5), pp.1051-1064.
2. Millar, J. (2000). Disruption of two novel genes by a translocation co-segregating with schizophrenia. Human Molecular Genetics, 9(9), pp.1415-1423.
3. Nagai, J., Baba, R. and Ohshima, T. (2016). CRMPs Function in Neurons and Glial Cells: Potential Therapeutic Targets for Neurodegenerative Diseases and CNS Injury. Molecular Neurobiology, 54(6), pp.4243-4256.
4. Taya, S., Shinoda, T., Tsuboi, D., Asaki, J., Nagai, K., Hikita, T., Kuroda, S., Kuroda, K., Shimizu, M., Hirotsune, S., Iwamatsu, A. and Kaibuchi, K. (2007). DISC1 Regulates the Transport of the NUDEL/LIS1/14-3-3 Complex through Kinesin-1. Journal of Neuroscience, 27(1), pp.15-26.
5. Sialana, F., Wang, A., Fazari, B., Kristofova, M., Smidak, R., Trossbach, S., Korth, C., Huston, J., de Souza Silva, M. and Lubec, G. (2018). Quantitative Proteomics of Synaptosomal Fractions in a Rat Overexpressing Human DISC1 Gene Indicates Profound Synaptic Dysregulation in the Dorsal Striatum. Frontiers in Molecular Neuroscience, 11.

 

Posted on: 19th December 2018

Read preprint (No Ratings Yet)




  • Have your say

    Your email address will not be published. Required fields are marked *

    This site uses Akismet to reduce spam. Learn how your comment data is processed.

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the neuroscience category:

    Blue light induces neuronal-activity-regulated gene expression in the absence of optogenetic proteins

    Kelsey M. Tyssowski, Jesse M. Gray



    Selected by Zheng-Shan Chong

    A pair of E3 ubiquitin ligases compete to regulate filopodial dynamics and axon guidance

    Nicholas P Boyer, Laura E McCormick, Fabio L Urbina, et al.



    Selected by Angika Basant

    1

    Prospective, brain-wide labeling of neuronal subclasses with enhancer-driven AAVs

    Lucas T Graybuck, Adriana Sedeño-Cortés, Thuc Nghi Nguyen, et al.



    Selected by Jesus Victorino

    SorCS1-mediated Sorting of Neurexin in Dendrites Maintains Presynaptic Function

    Luis Filipe Ribeiro, Ben Verpoort, Julie Nys, et al.



    Selected by Carmen Adriaens

    1

    Multilevel regulation of the glass locus during Drosophila eye development

    Cornelia Fritsch, F. Javier Bernardo-Garcia, Tim Humberg, et al.



    Selected by Gabriel Aughey

    1

    Regulation of modulatory cell activity across olfactory structures in Drosophila melanogaster

    Xiaonan Zhang, Kaylynn Coates, Andrew Dacks, et al.



    Selected by Rudra Nayan Das

    1

    On-site ribosome remodeling by locally synthesized ribosomal proteins in axons

    Toshiaki Shigeoka, Max Koppers, Hovy Ho-Wai Wong, et al.



    Selected by Srivats Venkataramanan

    Single cell RNA-Seq reveals distinct stem cell populations that drive sensory hair cell regeneration in response to loss of Fgf and Notch signaling

    Mark E. Lush, Daniel C. Diaz, Nina Koenecke, et al.

    AND

    Distinct progenitor populations mediate regeneration in the zebrafish lateral line.

    Eric D Thomas, David Raible



    Selected by Rudra Nayan Das

    2

    A schizophrenia risk gene, NRGN, bidirectionally modulates synaptic plasticity via regulating the neuronal phosphoproteome

    Hongik Hwang, Matthew J Szucs, Lei J Ding, et al.



    Selected by Laura McCormick

    Actomyosin-II facilitates long-range retrograde transport of large cargoes by controlling axonal radial contractility

    Tong Wang, Wei Li, Sally Martin, et al.



    Selected by Ivana Viktorinová

    Unlimited genetic switches for cell-type specific manipulation

    Jorge Garcia-Marques, Ching-Po Yang, Isabel Espinosa-Medina, et al.



    Selected by Rafael Almeida

    1

    Defining the design requirements for an assistive powered hand exoskeleton

    Quinn A Boser, Michael R Dawson, Jonathon S Schofield, et al.



    Selected by Joanna Cross

    Strong preference for autaptic self-connectivity of neocortical PV interneurons entrains them to γ-oscillations

    Charlotte Deleuze, Gary S Bhumbra, Antonio Pazienti, et al.



    Selected by Mahesh Karnani

    Distributed correlates of visually-guided behavior across the mouse brain

    Nicholas Steinmetz, Peter Zatka-Haas, Matteo Carandini, et al.



    Selected by Craig Bertram

    Psychiatric risk gene NT5C2 regulates protein translation in human neural progenitor cells

    Rodrigo R.R. Duarte, Nathaniel D. Bachtel, Marie-Caroline Cotel, et al.



    Selected by Joanna Cross

    1

    Single cell transcriptomics reveals spatial and temporal dynamics of gene expression in the developing mouse spinal cord

    Julien Delile, Teresa Rayon, Manuela Melchionda, et al.



    Selected by Reena Lasrado

    1

    Close