Benjamin L. Wolozin, MD, PhD
Professor, Pharmacology & Experimental Therapeutics
Biography
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.
Other Positions
- Professor, Neurology, Boston University Chobanian & Avedisian School of Medicine
- 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
Education
- Albert Einstein College of Medicine, MD
- Wesleyan University, BA
Publications
- Published on 12/1/2021
Rickner H, Jiang L, Hong R, Wolozin B, Cheng C. Single cell transcriptomic profiling of neurodegeneration mediated by tau in a novel 3D neuron-astrocyte coculture model. Alzheimers Dement. 2021 Dec; 17 Suppl 2:e058551. PMID: 34971136.
Read at: PubMed - Published on 10/23/2021
Zhang Z, Na H, Gan Q, Tao Q, Alekseyev Y, Hu J, Yan Z, Yang JB, Tian H, Zhu S, Li Q, Rajab IM, Blusztajn JK, Wolozin B, Emili A, Zhang X, Stein T, Potempa LA, Qiu WQ. Monomeric C-reactive protein via endothelial CD31 for neurovascular inflammation in an ApoE genotype-dependent pattern: A risk factor for Alzheimer's disease? Aging Cell. 2021 11; 20(11):e13501. PMID: 34687487.
Read at: PubMed - Published on 8/27/2021
Jiang L, Lin W, Zhang C, Ash PEA, Verma M, Kwan J, van Vliet E, Yang Z, Cruz AL, Boudeau S, Maziuk BF, Lei S, Song J, Alvarez VE, Hovde S, Abisambra JF, Kuo MH, Kanaan N, Murray ME, Crary JF, Zhao J, Cheng JX, Petrucelli L, Li H, Emili A, Wolozin B. Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy. Mol Cell. 2021 10 21; 81(20):4209-4227.e12. PMID: 34453888.
Read at: PubMed - Published on 3/2/2021
Ash PEA, Lei S, Shattuck J, Boudeau S, Carlomagno Y, Medalla M, Mashimo BL, Socorro G, Al-Mohanna LFA, Jiang L, Öztürk MM, Knobel M, Ivanov P, Petrucelli L, Wegmann S, Kanaan NM, Wolozin B. TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau. Proc Natl Acad Sci U S A. 2021 03 02; 118(9). PMID: 33619090.
Read at: PubMed - Published on 2/25/2021
Sindi S, Solomon A, Kåreholt I, Hovatta I, Antikainen R, Hänninen T, Levälahti E, Laatikainen T, Lehtisalo J, Lindström J, Paajanen T, Peltonen M, Singh Khalsa D, Wolozin B, Strandberg T, Tuomilehto J, Soininen H, Ngandu T, Kivipelto M. Telomere Length Change in a Multidomain Lifestyle Intervention to Prevent Cognitive Decline: A Randomized Clinical Trial. J Gerontol A Biol Sci Med Sci. 2021 02 25; 76(3):491-498. PMID: 33175128.
Read at: PubMed - Published on 1/7/2021
Hekman RM, Hume AJ, Goel RK, Abo KM, Huang J, Blum BC, Werder RB, Suder EL, Paul I, Phanse S, Youssef A, Alysandratos KD, Padhorny D, Ojha S, Mora-Martin A, Kretov D, Ash PEA, Verma M, Zhao J, Patten JJ, Villacorta-Martin C, Bolzan D, Perea-Resa C, Bullitt E, Hinds A, Tilston-Lunel A, Varelas X, Farhangmehr S, Braunschweig U, Kwan JH, McComb M, Basu A, Saeed M, Perissi V, Burks EJ, Layne MD, Connor JH, Davey R, Cheng JX, Wolozin BL, Blencowe BJ, Wuchty S, Lyons SM, Kozakov D, Cifuentes D, Blower M, Kotton DN, Wilson AA, Mühlberger E, Emili A. Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2. Mol Cell. 2021 Jan 07; 81(1):212. PMID: 33417854.
Read at: PubMed - Published on 12/29/2020
Basu A, Ash PE, Wolozin B, Emili A. Protein Interaction Network Biology in Neuroscience. Proteomics. 2021 02; 21(3-4):e1900311. PMID: 33314619.
Read at: PubMed - Published on 11/19/2020
Hekman RM, Hume AJ, Goel RK, Abo KM, Huang J, Blum BC, Werder RB, Suder EL, Paul I, Phanse S, Youssef A, Alysandratos KD, Padhorny D, Ojha S, Mora-Martin A, Kretov D, Ash PEA, Verma M, Zhao J, Patten JJ, Villacorta-Martin C, Bolzan D, Perea-Resa C, Bullitt E, Hinds A, Tilston-Lunel A, Varelas X, Farhangmehr S, Braunschweig U, Kwan JH, McComb M, Basu A, Saeed M, Perissi V, Burks EJ, Layne MD, Connor JH, Davey R, Cheng JX, Wolozin BL, Blencowe BJ, Wuchty S, Lyons SM, Kozakov D, Cifuentes D, Blower M, Kotton DN, Wilson AA, Mühlberger E, Emili A. Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2. Mol Cell. 2020 12 17; 80(6):1104-1122.e9. PMID: 33259812.
Read at: PubMed - Published on 9/30/2020
Jiang L, Zhao J, Cheng JX, Wolozin B. Tau Oligomers and Fibrils Exhibit Differential Patterns of Seeding and Association With RNA Binding Proteins. Front Neurol. 2020; 11:579434. PMID: 33101187.
Read at: PubMed - Published on 8/26/2020
Pourhaghighi R, Ash PEA, Phanse S, Goebels F, Hu LZM, Chen S, Zhang Y, Wierbowski SD, Boudeau S, Moutaoufik MT, Malty RH, Malolepsza E, Tsafou K, Nathan A, Cromar G, Guo H, Al Abdullatif A, Apicco DJ, Becker LA, Gitler AD, Pulst SM, Youssef A, Hekman R, Havugimana PC, White CA, Blum BC, Ratti A, Bryant CD, Parkinson J, Lage K, Babu M, Yu H, Bader GD, Wolozin B, Emili A. BraInMap Elucidates the Macromolecular Connectivity Landscape of Mammalian Brain. Cell Syst. 2020 Aug 26; 11(2):208. PMID: 32853540.
Read at: PubMed
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