Assistant Professor, Dominick P. Purpura Department of Neuroscience
Assistant Professor, Department of Psychiatry and Behavioral Sciences
An important question in neuroscience is how does neuronal activity alter neuronal connectivity. This question is critically important since changes in connectivity and transmission underlie higher order brain functions such as learning and memory and likely play a role in the cognitive deficits observed in many neurological diseases. To explore this question, we employ proteomics and mass spectrometry, which provide us with a global overview of synaptic and nuclear complexity and allow us to explore their dynamics. Using these methods, we found that a number of synaptic components can shuttle to the neuronal nucleus in response to synaptic activity. These include PRR7 and AIDA-1, which binds to NMDA receptors (NMDAR) and links synaptic activity to nuclear functions. Recent studies implicate AIDA-1 in diverse psychiatric and developmental disorders including schizophrenia and Autism spectrum disorders. A single nucleotide polymorphism (SNP) in the AIDA-1 gene (ANKS1b) is associated with response to antipsychotics, suggesting AIDA-1 may play a role in schizophrenia. Moreover copy number variations (CNVs) and SNPs of AIDA-1 have been identified in patients with autism and correlate positively with impaired play skills in ASD. Moreover we have recently found that AIDA-1 can regulate the metabolism of the Amyloid Precursor Protein (APP) in neurons. AIDA-1 can promote the generation of amyloid beta peptides by regulating APP internalization, and may therefore it may play an important role in Alzheimer’s disease.
Moreover we found that certain RNA binding proteins (RNABPs) shuttle back into synaptic junctions in response to neuronal activity. We have recently shown that one of these proteins, Sam68, regulates the synaptic and dendritic expression of beta-actin and is crucial for proper spine morphology and synaptic function. Sam68 has been recently implicated in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), which is a neurodegenerative disorder caused by mutations upstream of the FMR1 gene. We are therefore investigating if Sam68-dependent protein translation of cytoskeletal components can affect synaptic function and plasticity and ultimately behavior. We believe Sam68 plays a role in the generation and refining of neuronal networks. Understanding precisely how neurons regulate specific connections amongst their many thousand inputs is a central question in neuroscience. Therefore our lab employs broad-based proteomics methods to understand how synapses relay fast synaptic information to the nucleus and back, what are the key players in this process, and what role do these molecules play in brain pathologies.
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. mu opioid and alpha2a-adrenergic receptor interactions in neurons. 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. Opioid receptors heterodimerize with beta-adrenergic receptors: A role in trafficking and MAPK activation. PNAS 2001;98(1): 343-348.
Gomes I, Jordan BA, Nagy V, Trapaidze N, Bansinath M, and Devi LA. (2000) Interaction between Mu and Delta opioid receptors: A role for dimerization in opioid receptor cross-talk, 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 signaltransduction, Br J Anaesth 81, 12-19.
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