Jordan Lab

The mammalian brain is perhaps the most complex machine known. A close interplay of genetic and environmental influences cause 80 billion neurons to form 100 trillion connections, leading to an organ capable of thought, memory, and emotions. While much has been learned about the genetic factors that drive brain development, much remains unclear. We study how abnormalities in certain genes lead to brain disorders, focusing on neurons, glia, synapses, and nuclei.

Research

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.

REFERENCES:

Jacob, A. L., B. A. Jordan and R. J. Weinberg (2010). “Organization of amyloid-beta protein precursor intracellular domain-associated protein-1 in the rat brain.” J Comp Neurol 518(16): 3221-3236.
Jordan, B. A., B. D. Fernholz, M. Boussac, C. Xu, G. Grigorean, E. B. Ziff and T. A. Neubert (2004). “Identification and verification of novel rodent postsynaptic density proteins.” Mol Cell Proteomics 3(9): 857-871.
Jordan, B. A., B. D. Fernholz, L. Khatri and E. B. Ziff (2007). “Activity-dependent AIDA-1 nuclear signaling regulates nucleolar numbers and protein synthesis in neurons.” Nat Neurosci 10(4): 427-435.
Jordan, B. A. and M. R. Kreutz (2009). “Nucleocytoplasmic protein shuttling: the direct route in synapse-to-nucleus signaling.” Trends Neurosci 32(7): 392-401.
Klein, M. E., P. E. Castillo and B. A. Jordan (2015). “Coordination between Translation and Degradation Regulates Inducibility of mGluR-LTD.” Cell Rep.
Klein, M. E., T. J. Younts, P. E. Castillo and B. A. Jordan (2013). “RNA-binding protein Sam68 controls synapse number and local beta-actin mRNA metabolism in dendrites.” Proc Natl Acad Sci U S A 110(8): 3125-3130.
Klein, M. E., T. J. Younts, C. F. Cobo, A. R. Buxbaum, J. Aow, H. Erdjument-Bromage, S. Richard, R. Malinow, T. A. Neubert, R. H. Singer, P. E. Castillo and B. A. Jordan (2019). “Sam68 Enables Metabotropic Glutamate Receptor-Dependent LTD in Distal Dendritic Regions of CA1 Hippocampal Neurons.” Cell Rep 29(7): 1789-1799 e1786.
Kravchick, D. O., A. Karpova, M. Hrdinka, J. Lopez-Rojas, S. Iacobas, A. U. Carbonell, D. A. Iacobas, M. R. Kreutz and B. A. Jordan (2016). “Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity.” EMBO J 35(17): 1923-1934.
Tindi, J. O., A. E. Chavez, S. Cvejic, E. Calvo-Ochoa, P. E. Castillo and B. A. Jordan (2015). “ANKS1B Gene Product AIDA-1 Controls Hippocampal Synaptic Transmission by Regulating GluN2B Subunit Localization.” J Neurosci 35(24): 8986-8996.
Zhang, G., T. A. Neubert and B. A. Jordan (2012). “RNA binding proteins accumulate at the postsynaptic density with synaptic activity.” J Neurosci 32(2): 599-609.

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.

REFERENCES:

Carbonell, A. U., C. Freire-Cobo, I. V. 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.

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.

REFERENCES:

Carbonell, A. U., C. H. Cho, J. O. Tindi, P. A. Counts, J. C. Bates, H. Erdjument-Bromage, S. Cvejic, A. Iaboni, I. Kvint, J. Rosensaft, E. Banne, E. Anagnostou, T. A. Neubert, S. W. Scherer, S. Molholm and B. A. Jordan (2019). “Haploinsufficiency in the ANKS1B gene encoding AIDA-1 leads to a neurodevelopmental syndrome.” Nat Commun 10(1): 3529.
Jacob, A. L., B. A. Jordan and R. J. Weinberg (2010). “Organization of amyloid-beta protein precursor intracellular domain-associated protein-1 in the rat brain.” J Comp Neurol 518(16): 3221-3236.
Jordan, B. A., B. D. Fernholz, L. Khatri and E. B. Ziff (2007). “Activity-dependent AIDA-1 nuclear signaling regulates nucleolar numbers and protein synthesis in neurons.” Nat Neurosci 10(4): 427-435.
Tindi, J. O., A. E. Chavez, S. Cvejic, E. Calvo-Ochoa, P. E. Castillo and B. A. Jordan (2015). “ANKS1B Gene Product AIDA-1 Controls Hippocampal Synaptic Transmission by Regulating GluN2B Subunit Localization.” J Neurosci 35(24): 8986-8996.

People

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Selected Publications

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

Klein, M. E., T. J. Younts, C. F. Cobo, A. R. Buxbaum, J. Aow, H. Erdjument-Bromage, S. Richard, R. Malinow, T. A. Neubert, R. H. Singer, P. E. Castillo and B. A. Jordan (2019). “Sam68 Enables Metabotropic Glutamate Receptor-Dependent LTD in Distal Dendritic Regions of CA1 Hippocampal Neurons.” Cell Rep 29(7): 1789-1799 e1786.

Kravchick, D. O., A. Karpova, M. Hrdinka, J. Lopez-Rojas, S. Iacobas, A. U. Carbonell, D. A. Iacobas, M. R. Kreutz and B. A. Jordan (2016). “Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity.” EMBO J 35(17): 1923-1934.

Tindi, J. O., A. E. Chavez, S. Cvejic, E. Calvo-Ochoa, P. E. Castillo and B. A. Jordan (2015). “ANKS1B Gene Product AIDA-1 Controls Hippocampal Synaptic Transmission by Regulating GluN2B Subunit Localization.” J Neurosci 35(24): 8986-8996.

Klein, M. E., P. E. Castillo and B. A. Jordan (2015). “Coordination between Translation and Degradation Regulates Inducibility of mGluR-LTD.” Cell Rep.

Klein, M. E., T. J. Younts, P. E. Castillo and B. A. Jordan (2013). “RNA-binding protein Sam68 controls synapse number and local beta-actin mRNA metabolism in dendrites.” Proc Natl Acad Sci U S A 110(8): 3125-3130.

Zhang, G., T. A. Neubert and B. A. Jordan (2012). “RNA binding proteins accumulate at the postsynaptic density with synaptic activity.” J Neurosci 32(2): 599-609.

Jordan, B. A. and M. R. Kreutz (2009). “Nucleocytoplasmic protein shuttling: the direct route in synapse-to-nucleus signaling.” Trends Neurosci 32(7): 392-401.

Jordan, B. A., B. D. Fernholz, L. Khatri and E. B. Ziff (2007). “Activity-dependent AIDA-1 nuclear signaling regulates nucleolar numbers and protein synthesis in neurons.” Nat Neurosci 10(4): 427-435.

Jordan, B. A., B. D. Fernholz, M. Boussac, C. Xu, G. Grigorean, E. B. Ziff and T. A. Neubert (2004). “Identification and verification of novel rodent postsynaptic density proteins.” Mol Cell Proteomics 3(9): 857-871.

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Bryen A. Jordan

Albert Einstein College of Medicine
Dominick P. Purpura Department of Neuroscience
Rose F. Kennedy Center / Room 825
1300 Morris Park Avenue
Bronx, NY 10461

Email: bryen.jordan@einsteinmed.org
Tel: 718-430-2675