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Bryen A. Jordan, Ph.D.

Bryen A. Jordan, Ph.D.

Associate Professor, Dominick P. Purpura Department of Neuroscience

Associate Professor, Department of Psychiatry and Behavioral Sciences

Area of Research: Synaptic plasticity; RNA transport and local translation; synapse-to-nucleus signaling; Proteomic analysis of synaptic junctions; Neurodevelopmental disorders; ANKS1B haploinsufficiency syndrome.

Contact Information

718.430.2675bryen.jordan@einsteinmed.org

Albert Einstein College of Medicine
Rose F. Kennedy Center
1410 Pelham Parkway South, Room 825
Bronx, NY 10461

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Professional Interests

Understanding mechanisms that regulate long-term changes in neuronal function

Long-term changes in neuronal function require the regulation of gene expression. Studies initiated in the 1960s and onward have established that transcription is required for the establishment and consolidation of long-term memories in diverse organisms. Cellular processes linking neural communication to gene expression include the rapid influx of calcium into the nucleus and the nucleocytoplasmic shuttling of a broad array of proteins that specify the nuclear signal. Our lab is interested in identifying and characterizing the mechanisms linking specific synaptic activity to gene expression. To explore this question, we performed one of the first comprehensive proteomic analyses of rodent synapses (postsynaptic density fractions) and found that they are highly complex and contain proteins that can shuttle into the nucleus following synaptic activity (Jordan et al. 2004). We have studied several of these nuclear signaling molecules, including the novel synaptic component PRR7, which can shuttle into the nucleus and regulate c-Jun dependent transcription by controlling ubiquitination (Kravchick et al. 2016). A second protein we study is AIDA-1, which binds to NMDARs and controls nucleolar function (Jordan et al. 2007, Jacob et al. 2010, Tindi et al. 2015). These studies have provided some of the first evidence of direct synapse-to-nucleus communication and demonstrate that this process is an important cellular mechanism that can tailor and translate synaptic information into changes in gene expression (Jordan and Kreutz 2009).

Novel activity-dependent transcripts must then be localized within complex neuronal morphologies to provide synapse-specific regulation of function. RNA binding proteins (RNABPs) transport and translate specific mRNAs to enable the precise spatiotemporal expression of proteins across neurons. This process enables input-specific regulation of synaptic function and is essential for proper circuit regulation and brain function. Loss of RNABP activity is causal in a wide range of neurodegenerative and developmental disorders including Fragile X Syndrome (FXS), hereditary forms of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (FTD), intellectual disabilities, and epilepsy. We performed the first quantitative proteome-wide analyses of activity-dependent changes at synaptic junctions and found that diverse RNA binding proteins (RNABPs) were among the most altered protein families at synapses (Zhang et al. 2012). Indeed, 12 of 37 identified proteins whose levels changed with synaptic activity were RNABPs and included the heterogeneous nuclear ribonucleoproteins (hnRNPs) G, A2/B1, M, and D. Among these proteins was Sam68, a multifunctional RBP with reported roles in mRNA transport, translation, and alternative splicing. We found that Sam68 promotes the localization and translation of beta-actin (Klein et al. 2013), and Arc mRNA preferentially at distal dendrites of rodent hippocampal CA1 pyramidal neurons (Klein et al. 2015, Klein et al. 2019). Sam68 knockout mice display impaired metabotropic glutamate-receptor-dependent long-term depression (mGluR-LTD) and impaired structural plasticity exclusively at distal Schaffer-collateral synapses. Our work identifies an important player in Arc expression, provides a general framework for Sam68 regulation of protein synthesis, and uncovers a mechanism that enables the precise spatiotemporal expression of proteins that regulate long-term plasticity throughout neurons.

Using proteomics to understand Autism Spectrum Disorders

Autism spectrum disorders (ASDs) are highly complex and prevalent neurodevelopmental diseases with enormous social and economic impacts. Despite intense research into ASD pathophysiology, few available therapies exist due to a poor understanding of causative molecular and cellular mechanisms. The advent and use of next generation sequencing and genome wide association (GWAS) studies in humans have yielded many hundred ASD susceptible chromosomal loci and genes. While these targets have provided a wealth of minable information, this highly complex genetic architecture has hampered ongoing efforts to elucidate causal molecular pathways and to develop diagnostic tests and targeted therapies. A critical barrier is an incomplete understanding of how single nucleotide polymorphisms or variants (SNPs, SNVs), copy number variations (CNVs), or altered transcript abundance ultimately regulate protein abundance and cellular function. Moreover, widespread discrepancies between transcript and protein abundance strongly limit the usefulness of genomic information. Transcriptomes can display 100-fold ranges in translation efficiency, and proteins reveal >1000-fold ranges in half-lives. Moreover, coupled transcriptome-proteome analyses reveal that proteins are ~900 times more abundant than corresponding mRNAs, but with ratios spanning five orders of magnitude. Genomic studies are also unlikely to provide significant information on diseases such as Angelman, Fragile X, and Tuberous sclerosis that are caused by dysfunction of regulators of protein translation and degradation. Despite these roadblocks, functional and bioinformatic analyses of genetic studies have identified potential convergent cellular pathways in ASD etiology, including those regulating transcription, excitatory/inhibitory (E/I) balance, and especially synaptic function.

We employ quantitative proteomic methods to elucidate molecular and cellular mechanisms underlying ASDs and other brain disorders. Our approach overcomes critical confounds associated with gene-based studies that ambiguously equate transcript levels, epigenetic modifications, SNVs, or CNVs to changes in protein abundance. Specifically, our lab is testing the hypothesis that ASD-linked susceptibility factors ultimately converge on a common signaling pathway regulating synaptic function, and that this point of convergence is key to understanding disease pathobiology. We propose that synaptic proteomes, as phenotypes of diverse ASD manifestations, capture the combined influences of genetic, epigenetic, transcriptomic, proteomic and environmental influences linked to ASD etiology. In our work, we leverage the availability of multiple ASD mouse models exhibiting shared synaptic deficits and behavioral correlates of autism and employ quantitative proteomic approaches to compare different syndromic and nonsyndromic ASD mouse models (Carbonell et al. 2021), as well as human ASD postmortem tissue. Results are then mined using network and systems biology approaches to identify shared cellular and molecular abnormalities. We hypothesize that identifying points of convergence will lead to important insights into ASD etiology and will yield high-value targets for pursuing therapies.

ANKS1B haploinsufficiency in a novel brain disorder

Neurodevelopmental disorders (NDDs) are highly prevalent brain diseases with enormous social and economic impacts. Due to their high heritability, numerous efforts are underway to identify causative genetic signatures. Genome-wide association studies and the advent and use of genetic screening in clinical settings have enabled rapid progress in identifying genes and other chromosomal loci linked to NDDs. However, these studies have revealed a highly heterogeneous genetic landscape consisting mainly of variants with statistically minor contributions to disease risk, and with unclear or minor effects on protein function. These uncertainties hinder attempts to infer causative molecular mechanisms. On the other hand, structural variants with major effects on single gene function are particularly useful as they establish a stronger link between one gene and a set of cellular and behavioral outcomes. We recently identified individuals in Israel, Australia, France, England, Ireland and the USA with heterozygous and monogenic copy number variations in the ANKS1B gene. Clinical evaluations reveal that patients exhibit a spectrum of NDDs, including ADHD, motor impairments, speech apraxia, and autism, which is present in >50% of patients. Whole-genome and exome sequencing analyses of patient samples identify no other confounding genetic variations potentially associated with disease. Our findings corroborate previous genome-wide and genetic studies implicating ANKS1B in brain disorders and formalize a link between ANKS1B haploinsufficiency and a previously uncharacterized NDD that we term ANKS1B haploinsufficiency syndrome (AnkSyd).

We have generated induced pluripotent stem cells (iPSCs), neurons, and brain organoids from patients and unaffected family members to elucidate cellular and molecular mechanisms underlying AnkSyd. We have also generated transgenic mouse models that display behavioral correlates of patient phenotypes (Carbonell et al. 2019). We find that neurons derived from patients show reduced expression of AIDA-1, the protein encoded by ANKS1B. AIDA-1 is one of the most abundant proteins at neuronal synapses and is enriched in hippocampal and cerebellar regions (Jordan et al. 2007, Jacob et al. 2010). AIDA-1 is specifically localized at postsynaptic densities (PSDs) where it binds to N-methyl-D-aspartate receptors (NMDARs) and the scaffolding protein PSD95, and shuttles to the nucleus in response to NMDAR stimulation (Jordan et al. 2007). Forebrain-specific Anks1b knockout mice show reduced synaptic expression of the NMDAR subunit GluN2B and impaired hippocampal NMDA-dependent synaptic plasticity (Tindi et al. 2015). The long-term goal of this research project is to define the mechanisms underlying this novel syndrome and to identify therapeutic targets.ANKS1B encodes for AIDA-1, a brain-specific protein that we have shown is enriched at neuronal synapses, and binds to and regulates NMDAR subunit composition and NMDAR-dependent synaptic plasticity. Our objectives are to test NMDAR function in patient neurons, elucidate mechanisms linking AIDA-1 to NMDAR function, and identify disease-relevant molecular pathways using discovery-based and reductionist approaches.

Selected Publications

Carbonell, A. U., C. Freire-Cobo, I. U. Deyneko, H. Erdjument-Bromage, A. E. Clipperton-Allen, R. L. Rasmusson, D. T. Page, T. A. Neubert and B. A. Jordan (2021). "Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling." bioRxiv.

Monday HR, Bourdenx M, Jordan BA, Castillo PE. CB1 receptor-mediated inhibitory LTD triggers presynaptic remodeling via protein synthesis and ubiquitination. eLife Sept 9, 2020; DOI: 10.7554

Ratnakumar A, Zimmerman SE, Jordan BA, Mar JC. Estrogen activates Alzheimer's disease genes. Alzheimers Dement (NY) 2019 Dec 9; 5:906-917

Younts TJ, Monday HR, Dudok B, Klein ME, Jordan BA, Katona I, Castillo PE. Presynaptic protein synthesis is required for long-term plasticity of GABA release. Neuron 2016 Oct 19; 92(2):479-492

Kravchick DO, Karpova A, Hrdinka M, Lopez-Rojas J, Iacobas S, Carbonell AU, Iacobas DA, Kreutz MR, Jordan BA. Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA mediated excitotoxicity. The EMBO Journal. 2016 Sep 1;35(17):1923-34

Tindi JO, Chávez AE, Cvejic S, Calvo-Ochoa E, Castillo PE, Jordan BA. ANKS1B Gene Product AIDA-1 Controls Hippocampal Synaptic Transmission by Regulating GluN2B Subunit Localization. J. Neurosci.2015 Jun 17;35 (24), 8986-8996

Kravchick DO, Jordan BA. Presynapses go nuclear! EMBO J. 2015 Apr 15;34(8):984-6.

KleinME, Castillo PE, Jordan BA. Coordination between Translation and Degradation Regulates Inducibility of mGluR-LTD. Cell Reports 2015 Mar 10;(10):1459-1466

Klein ME, Younts TJ, Castillo PE, Jordan BA. RNA-binding protein Sam68 controls synapse number and local β-actin mRNA metabolism in dendrites. PNAS 2013 Feb 19;110(8):3125-30

Mulholland PJ, Jordan BA, Chandler LJ. Chronic ethanol up-regulates the synaptic expression of the nuclear translational regulatory protein AIDA-1 in primary hippocampal neurons. Alcohol. 2012 Sep;46(6):569-76.

Zhang G, Neubert TA, Jordan BA. RNA binding proteins accumulate at the postsynaptic density with synaptic activity. J Neurosci. 2012 Jan 11:32(2): 599-609.

Jacob AL, Jordan BA, Weinberg RJ. Organization of amyloid-beta protein precursor intracellular domain-associated protein-1 in the rat brain. J Comp Neurol. 2010 Aug 15;518(16):3221-36.

Jordan BA, Kreutz MR. Nucleocytoplasmic protein shuttling: the direct route in synapse-to-nucleus signaling. Trends in Neurosci (TINS). 2009 Jul;32(7):392-401.

Jordan BA, Ziff EB. To the Nucleus with Proteomics. In Regulation of Transcription by Neuronal Activity. Edited by: Dudek SM. Springer Science;November 2007.

Jordan BA, Fernholz BD, Khatri L, Ziff EB. Activity-dependent AIDA-1 nuclear signaling regulates nucleolar numbers and protein synthesis in neurons. Nat. Neurosci. 2007 Apr; 10(4):427-35.

Jordan BA, Fernholz BD, Neubert TA, Ziff EB: New Tricks for an Old Dog: Proteomics of the PSD. In The Dynamic Synapse: Molecular Methods in Ionotropic Receptor Biology. Volume 29. Edited by: Kittler JT, Moss SJ. Boca Raton: CRC/Taylor & Francis; 2006:37-55.

Jordan BA, Ziff EB. Getting to synaptic complexes through systems biology. Genome Biology, 2006 7:214. doi:10.1186/gb-2006-7-4-214.

Monea S, Jordan BA, Srivastava S, DeSouza S, and Ziff EB. Membrane localization of membrane type 5 matrix metalloproteinase by AMPA receptor binding protein and cleavage of cadherins. J. Neurosci. 2006 26: 2300-2312.

Jordan BA, Fernholz BD, Boussac M, Xu C, Grigorean G, Ziff EB, Neubert TA. Identification and verification of novel rodent postsynaptic density proteins. Mol Cell Proteomics. 2004 Sep; 3(9): 857-71.

Jordan BA, Gomes I, Rios CD, Filipovska J, Devi L. Functional interactions between mu opioid and alpha 2A-adrenergic receptors. Mol Pharm 2003; Dec; 64(6): 1317-24.

Gomes I, Filipovska J, Jordan BA, Devi LA. Oligomerization of opioid receptors. Methods 27 (4): 358-365 Aug 2002.

Rios CD, Jordan BA, Gomes I, and Devi LA. G-protein-coupled receptor dimerization: modulation of receptor function. Pharmacol Therapeut 92 (2-3): 71-87 Nov-Dec 2001.

Gomes I, Jordan BA, Gupta A, Rios C, Trapaidze N, Devi LA. G protein coupled receptor dimerization: implications in modulating receptor function. Journal of Mol Med 79 (5-6): 226-242 Jun 2001.

Jordan BA, Trapaidze N, Gomes I, Nivarthi R, and Devi LA. Oligomerization of opioid receptors with beta 2-adrenergic receptors: a role in trafficking and mitogen-activated protein kinase activation. PNAS 2001;98(1): 343-348.

Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, and Devi LA. (2000) Heterodimerization of mu and delta opioid receptors: A role in opiate synergy. J Neurosci 20: RC110.

Jordan BA, Cvejic S, and Devi LA. (2000). Kappa opioid receptor endocytosis by dynorphin peptides. DNA Cell Biol 19, 19-27.

Jordan BA, Cvejic S, and Devi LA. (2000). Opioids and their complicated receptor complexes. Neuropsychopharmacology 19, 19-27.

Jordan BA, and Devi LA. (1999). G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399, 697-700.

Jordan B, and Devi LA. (1998). Molecular mechanisms of opioid receptor signal transduction. Br J Anaesth 81, 12-19.

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Bryen A. Jordan, Ph.D.

Contact Information

Professional Interests

Selected Publications

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