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.
- Member, Evans Center for Interdisciplinary Biomedical Research, Boston University
- Member, Genome Science Institute, Boston University
- Graduate Faculty (Primary Mentor of Grad Students), Boston University Chobanian & Avedisian School of Medicine, Graduate Medical Sciences
- Wesleyan University, BA
- Albert Einstein College of Medicine, MD/PhD
- MM 707
- PM 700
- PM 932
- Published on 10/4/2023
Webber CJ, Murphy CN, Rondón-Ortiz AN, van der Spek SJF, Kelly EX, Lampl NM, Chiesa G, Khalil AS, Emili A, Wolozin B. Human herpesvirus 8 ORF57 protein is able to reduce TDP-43 pathology: network analysis identifies interacting pathways. Hum Mol Genet. 2023 Oct 04; 32(20):2966-2980. PMID: 37522762.
- Published on 7/19/2023
Park J, Wu Y, Shao W, Gendron TF, van der Spek SJF, Sultanakhmetov G, Basu A, Castellanos Otero P, Jones CJ, Jansen-West K, Daughrity LM, Phanse S, Del Rosso G, Tong J, Castanedes-Casey M, Jiang L, Libera J, Oskarsson B, Dickson DW, Sanders DW, Brangwynne CP, Emili A, Wolozin B, Petrucelli L, Zhang YJ. Poly(GR) interacts with key stress granule factors promoting its assembly into cytoplasmic inclusions. Cell Rep. 2023 Aug 29; 42(8):112822. PMID: 37471224.
- Published on 6/15/2023
Zhao J, Jiang L, Matlock A, Xu Y, Zhu J, Zhu H, Tian L, Wolozin B, Cheng JX. Mid-infrared chemical imaging of intracellular tau fibrils using fluorescence-guided computational photothermal microscopy. Light Sci Appl. 2023 Jun 15; 12(1):147. PMID: 37322011.
- Published on 5/18/2023
Jiang L, Roberts R, Wong M, Zhang L, Webber CJ, Kilci A, Jenkins M, Sun J, Sun G, Rashad S, Dedon PC, Daley SA, Xia W, Ortiz AR, Dorrian L, Saito T, Saido TC, Wolozin B. Accumulation of m6A exhibits stronger correlation with MAPT than ß-amyloid pathology in an APPNL-G-F /MAPTP301S mouse model of Alzheimer's disease. Res Sq. 2023 May 18. PMID: 37292629.
- Published on 3/28/2023
Jiang L, Roberts R, Wong M, Zhang L, Webber CJ, Kilci A, Jenkins M, Sun G, Rashad S, Sun J, Dedon PC, Daley SA, Xia W, Ortiz AR, Dorrian L, Saito T, Saido TC, Wolozin B. Accumulation of m 6 A exhibits stronger correlation with MAPT than ß-amyloid pathology in an APP NL-G-F /MAPT P301S mouse model of Alzheimer's disease. bioRxiv. 2023 Mar 28. PMID: 37034774.
- Published on 2/23/2023
Zhao J, Jiang L, Matlock A, Xu Y, Zhu J, Zhu H, Tian L, Wolozin B, Cheng JX. Mid-infrared Chemical Imaging of Intracellular Tau Fibrils using Fluorescence-guided Computational Photothermal Microscopy. ArXiv. 2023 Feb 23. PMID: 36866226.
- Published on 2/16/2023
Puri S, Hu J, Sun Z, Lin M, Stein TD, Farrer LA, Wolozin B, Zhang X. Identification of circRNAs linked to Alzheimer's disease and related dementias. Alzheimers Dement. 2023 Aug; 19(8):3389-3405. PMID: 36795937.
- Published on 2/1/2023
Jiang L, Chakraborty P, Zhang L, Wong M, Hill SE, Webber CJ, Libera J, Blair LJ, Wolozin B, Zweckstetter M. Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress. Sci Adv. 2023 Feb 03; 9(5):eadd9789. PMID: 36724228.
- Published on 10/21/2022
Rickner HD, Jiang L, Hong R, O'Neill NK, Mojica CA, Snyder BJ, Zhang L, Shaw D, Medalla M, Wolozin B, Cheng CS. Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model. Nat Commun. 2022 Oct 21; 13(1):6275. PMID: 36271092.
- Published on 8/19/2022
Masi M, Attanzio A, Racchi M, Wolozin B, Borella S, Biundo F, Buoso E. Proteostasis Deregulation in Neurodegeneration and Its Link with Stress Granules: Focus on the Scaffold and Ribosomal Protein RACK1. Cells. 2022 Aug 19; 11(16). PMID: 36010666.
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