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Research Expertise & Professional Interests Dr. Wolozin’s research examines the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease, Amyotrophic Lateral Sclerosis and Parkinson’s disease. His laboratory is currently focused on the role of RNA binding proteins and translational regulation in disease processes. Parkinson’s disease: The research on Parkinson Disease focuses on genetic factors implicated in Parkinson’s disease, including LRRK2, a-synuclein, parkin, PINK1 and DJ-1. Research in our laboratory suggests that genetic mutations linked to Parkinson’s disease act by converging on a biological system that integrates the stress response, regulating autophagy, protein translation and mitochondrial function. Using genetically modified cells (e.g., primary neuronal cultures or cell lines) and genetically modified animals (C. elegans and mice), we have demonstrated that a-synuclein and LRRK2 enhance the sensitivity of dopaminergic neurons to mitochondrial dysfunction. Our work points to particular biochemical pathways mediating the actions of LRRK2. We have recently demonstrated that LRRK2 binds to MKK6, a kinase that lies upstream of p38 and regulates the stress response. LRRK2 regulates membrane localization of its binding proteins, including MKKs, JIPs, rac1 (a small GTPase) and other important proteins mediating the stress response. This work has direct relevance to therapy because it points to chemicals that might protect dopaminergic neurons and modify the course of Parkinson’s disease. For instance, we are investigating the action of SirT1 agonists (such resveratrol, the compound found in red wine or SRT1720, produced by Sirtris Pharmaceuticals), which stimulate synthesis of anti-oxidant enzymes and appear to offer protection in animal models of Parkinson’s disease. We are also investigating the action of brain penetrant analogues of rapamycin, which stimulate the neuron to remove protein aggregates, and offer neuroprotection through mechanisms complementary to SirT1. Amyotrophic Lateral Sclerosis (ALS): Our current work focuses on a protein, TDP-43, that was recently shown to be the predominant protein that accumulates during the course of the disease. We have shown that TDP-43 is a stress granule protein, and that TDP-43 pathology co-localizes with other stress granule markers in spinal cords of subjects with ALS, as well as those with Frontotemporal Dementia. We are currently examining how TDP-43 and disease-linked mutations in TDP-43 modify synaptic function in neuronal arbors. We are using protein binding assays (immunoprecipitation, mass spectrometry) and imaging assay (fixed cells and live cell imaging) to determine the effects of TDP-43 and its mutations. We use cell lines, primary cultures of hippocampal neurons and human brain samples for our studies. We also have an active drug discover program related to TDP-43. This program utilizes cells that inducibly over-express TDP-43, as well as lines of C. elegans expressing TDP-43 and studies in primary cultures of hippocampal neurons. We examine the compounds using imaging (in collaboration with Marcie Glicksman at LDDN) and biochemistry. Alzheimer disease (AD): We have recently extended our work on stress granules to Alzheimer’s disease. As with ALS, we have shown that tau pathology (neurofibrillary tangles) in the AD brain co-localizes with stress granule markers. The amount of stress granule pathology in the AD brain is very striking. Proteins such as TIA-1, G3BP and TTP, strongly accumulate. Interestingly, though, the pattern of accumulation differs based on the stress granule protein. The pathology appears to correlate with binding to tau protein. TIA-1 and TTP both bind to tau, while G3BP does not bind tau. Stress granules might also directly modulate tau pathology, because co-transfecting TIA-1 with tau induces formation of phosphorylated tau inclusions. The work on AD and stress granules uses biochemical/immunochemical studies focusing on proteins implicated in AD (e.g., antibodies to tau) and on stress granule markers. The work also uses extensive imaging assays (fixed cells, live cell imaging, confocal microscopy). We use studies of hippocampal neurons grown culture, transgenic mice expressing P301L tau and human tissues.
Self-Described Keywords cell culture
Self-Described Keywords induced pluripotent stem cells
Self-Described Keywords live cell imaging

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Concept Cell Compartmentation
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Concept Cell Division
Concept Cell Extracts
Concept Cell Line
Concept Cell Line, Transformed
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Concept Cells, Cultured
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Concept Receptors, Cell Surface
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Concept Cell Adhesion Molecules
Concept PC12 Cells
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Concept Neural Cell Adhesion Molecules
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Academic Article Transforming growth factor beta induces a beta-responsive calcium fluxes in neurons.
Academic Article Human olfactory neuroepithelial cells: tyrosine phosphorylation and process extension are increased by the combination of IL-1beta, IL-6, NGF, and bFGF.
Academic Article Physiological levels of beta-amyloid peptide promote PC12 cell proliferation.
Academic Article Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation.
Academic Article Changes in gene transcription during a beta-mediated cell death.
Academic Article FGF2 suppresses neuronogenesis of a cell line derived from rat olfactory epithelium.
Academic Article Differential regulation of APP secretion by apolipoprotein E3 and E4.
Academic Article Physiologic levels of beta-amyloid activate phosphatidylinositol 3-kinase with the involvement of tyrosine phosphorylation.
Academic Article Physiological levels of beta-amyloid peptide stimulate protein kinase C in PC12 cells.
Academic Article Amyloid precursor protein requires the insulin signaling pathway for neurotrophic activity.
Academic Article Direct association of presenilin-1 with beta-catenin.
Academic Article Beta-amyloid augments platelet aggregation: reduced activity of familial angiopathy-associated mutants.
Academic Article Regulation of apoptosis by presenilin 1.
Academic Article FMR1 gene expression in olfactory neuroblasts from two males with fragile X syndrome.
Academic Article alpha-Synuclein shares physical and functional homology with 14-3-3 proteins.
Academic Article Regulation of amyloid precursor protein processing by presenilin 1 (PS1) and PS2 in PS1 knockout cells.
Academic Article The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity.
Academic Article Parkin is metabolized by the ubiquitin/proteosome system.
Academic Article Mechanisms of neurodegenerative disorders: Part 1: protein aggregates.
Academic Article Mechanisms of neurodegenerative disorders: Part 2: control of cell death.
Academic Article Presenilin 1 regulates beta-catenin-mediated transcription in a glycogen synthase kinase-3-independent fashion.
Academic Article Co-association of parkin and alpha-synuclein.
Academic Article Continuous culture of neuronal cells from adult human olfactory epithelium.
Academic Article Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons.
Academic Article Hypoxia enhances beta-amyloid-induced apoptosis in rat cultured hippocampal neurons.
Academic Article alpha-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells.
Academic Article Differential expression of carboxyl terminal derivatives of amyloid precursor protein among cell lines.
Academic Article Beta/A4 domain of APP: antigenic differences between cell lines.
Academic Article Aggregated and monomeric alpha-synuclein bind to the S6' proteasomal protein and inhibit proteasomal function.
Academic Article CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation.
Academic Article Oxidative damage in cultured human olfactory neurons from Alzheimer's disease patients.
Academic Article SEPT5_v2 is a parkin-binding protein.
Academic Article Differential expression of cholesterol hydroxylases in Alzheimer's disease.
Academic Article beta-Synuclein reduces proteasomal inhibition by alpha-synuclein but not gamma-synuclein.
Academic Article The players on the gamma-secretase team.
Academic Article Leucine-rich repeat kinase 2 induces alpha-synuclein expression via the extracellular signal-regulated kinase pathway.
Academic Article The Parkinson's disease associated LRRK2 exhibits weaker in vitro phosphorylation of 4E-BP compared to autophosphorylation.
Academic Article MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2.
Academic Article LRRK2 and the stress response: interaction with MKKs and JNK-interacting proteins.
Academic Article Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue.
Academic Article Pathogenic LRRK2 mutations do not alter gene expression in cell model systems or human brain tissue.
Academic Article Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2).
Academic Article Characterization of insulin degrading enzyme and other amyloid-ß degrading proteases in human serum: a role in Alzheimer's disease?
Academic Article Correction: Pathogenic LRRK2 Mutations Do Not Alter Gene Expression in Cell Model Systems or Human Brain Tissue.
Academic Article The heat shock transcription factor Hsf1 is downregulated in DNA damage-associated senescence, contributing to the maintenance of senescence phenotype.
Academic Article Neuronal-specific overexpression of a mutant valosin-containing protein associated with IBMPFD promotes aberrant ubiquitin and TDP-43 accumulation and cognitive dysfunction in transgenic mice.
Academic Article Live Report: Rally to Restore Sanity and/or Fear, a Plea for Reason
Academic Article Neuronal Loss and Aging in Cellular Aging and Cell Death
Academic Article Classification of multiple morphine and enkephalin binding sites in the central nervous system.
Academic Article Physiological levels of beta-amyloid increase tyrosine phosphorylation and cytosolic calcium.
Academic Article A.E. Bennett Research Award 1993. Olfactory neuroblasts from Alzheimer donors: studies on APP processing and cell regulation.
Academic Article Induced pluripotent stem cell modeling of multisystemic, hereditary transthyretin amyloidosis.
Academic Article A Parkinson''s disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity.
Academic Article A high-content screen identifies novel compounds that inhibit stress-induced TDP-43 cellular aggregation and associated cytotoxicity.
Academic Article LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts.
Academic Article Syk and Yea Shall Find.
Academic Article Simvastatin inhibits protein isoprenylation in the brain.
Academic Article Pathological Tau Promotes Neuronal Damage by Impairing Ribosomal Function and Decreasing Protein Synthesis.
Academic Article Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity.
Academic Article Impairment of PARK14-dependent Ca(2+) signalling is a novel determinant of Parkinson''s disease.
Academic Article Increased cytoplasmic TDP-43 reduces global protein synthesis by interacting with RACK1 on polyribosomes.
Academic Article Dioxins and related environmental contaminants increase TDP-43 levels.
Academic Article Protein Phase Separation: A New Phase in Cell Biology.
Academic Article Directed evolution of a picomolar-affinity, high-specificity antibody targeting phosphorylated tau.
Academic Article Changes in neuronal immunofluorescence in the C- versus N-terminal domains of hnRNP H following D1 dopamine receptor activation.
Academic Article RNA binding proteins co-localize with small tau inclusions in tauopathy.
Academic Article Heavy Metal Neurotoxicants Induce ALS-Linked TDP-43 Pathology.
Academic Article TIA1 regulates the generation and response to toxic tau oligomers.
Academic Article Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology.
Academic Article Effects of Amylin Against Amyloid-ß-Induced Tauopathy and Synapse Loss in Primary Neurons.
Academic Article Dysregulation of RNA Splicing in Tauopathies.
Academic Article BraInMap Elucidates the Macromolecular Connectivity Landscape of Mammalian Brain.
Academic Article BraInMap Elucidates the Macromolecular Connectivity Landscape of Mammalian Brain.

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