Benjamin Wolozin, M.D., Ph.D.
Professor of Pharmacology and Neurology
Department of Pharmacology
M.D., Ph.D.: Albert Einstein College of Medicine
Pathophysiology of Neurodegeneration: Molecular and cellular Biology
Overview: The goal of our research is to understand the mechanisms underlying neurodegenerative diseases, and then to use this understanding to develop novel interventions for disease. Much of our research focuses on the central concept of regulated protein aggregation. Protein aggregation in neurodegenerative diseases is classically thought to occur as an unwanted byproduct of protein misfolding. Human genetic studies increasingly highlight the importance of RNA binding proteins in neurodegenerative diseases. This is important because RNA binding proteins use protein aggregation as part of a normal regulated, physiological mechanism controlling protein synthesis. Aggregated RNA binding proteins for stress granules, transport granules, P bodies, as well as participate in physiological functions, such as activity dependent protein synthesis. Our research investigates the hypothesis that dysfunction of RNA granules causes neurodegenerative diseases. Over active stress granule formation could contribute to neurodegeneration by altering patterns of protein synthesis and sequestering proteins that regulate cell death processes. Hypo-active stress granules, leads to inadequate neuroprotection.
Amyotrophic Lateral Sclerosis (ALS): Our studies of TDP-43 highlight the role of stress granules and other RNA granules in disease, and has driven our understanding of the role of regulated protein aggregation in disease. TDP-43 is an RNA binding protein that is the predominant protein that accumulates in the cytoplasm of neurons during the course of the disease. We have found that stress causes TDP-43 to migrate from the nucleus to the cytoplasm to form RNA inclusions termed stress granules. This work led to the discovery that the pathological inclusions in ALS co-localize with stress granule markers and enhance stress granule formation; we refer to these large, persistent stress granules as “pathological stress granules”. Neurons also use RNA granules to transport mRNA from the soma to the synapse; the requirement for RNA granules in transport leads to large amounts of aggregated RNA binding proteins in the cytoplasm, which might account for the propensity of mutations in RNA binding proteins to cause neurodegenerative disease. Indeed, our recent studies show that disease-linked mutations in TDP-43 cause changes in neuronal RNA granules that are evident at the earliest stages in the disease process; RNA granules carrying mutant TDP-43 are enlarged and move abnormally slowly.
Novel Therapeutic Approaches to ALS: Our ALS program also includes an exciting drug discovery effort. We have identified numerous novel compounds that are able to prevent and possibly reverse formation of pathological stress granules caused by expression of TDP-43 carrying disease-linked mutations. These compounds disperse pathological stress granules, solubilize mutant TDP-43 and send it back to the nucleus. We are currently seeking to identify the targets of action of these compounds, and validating the actions of the compounds in animal models.
For information on our research in Alzheimer’s or Parkinson’s disease, click on “Other Research”.
Alzheimer disease: Dr. Wolozin was recently given the Zenith Award to propel his studies of the roles of RNA binding proteins in Alzheimer’s disease. We recently discovered that the Alzheimer brain is characterized by massive accumulation of RNA binding proteins causing pathological stress granules. The discovery of the roles of RNA binding protein in the pathophysiology of Alzheimer’s disease suggests that aggregation of the microtubule associated tau protein might be controlled by regulated protein aggregation and the biology of RNA binding proteins. Since there are about 800 RNA binding proteins, the vast array of aggregating proteins provides new targets for therapeutic intervention and new approaches to image the disease process. Indeed, we find that some RNA binding proteins, such as TIA-1, strongly co-localize with tau/neurofibrillary tangles, while other RNA binding proteins, such as G3BP-1, accumulate in neurons that exhibit little if any tau pathology. Could it be that the same factors that disperse RNA stress granules can also disperse neurofibrillary tangles?
Parkinson’s disease: The research on Parkinson Disease focuses on genetic factors implicated in Parkinson’s disease, including LRRK2, α-synuclein, parkin and DJ-1. Research in our laboratory suggests that genetic mutations linked to Parkinson’s disease converge onto two main cellular pathways, mitochondrial function or management of misfolded proteins Using genetically modified cells (e.g., primary neuronal cultures or cell lines) and genetically modified animals (C. elegans and transgenic mice), we have demonstrated that LRRK2 enhances the sensitivity of dopaminergic neurons to toxins such as rotenone, a mitochondrial inhibitor, and we are currently investigating fascinating interactions between mitochondrial functions and autophagy. Our work also suggests particular biochemical pathways that mediate the actions of LRRK2. We have have found that LRRK2 binds to MKK6, a kinase that lies upstream of p38 and regulates the stress response. We also discovered that LRRK2 binds rac1, which is a small GTPase; binding to rac1 translocates LRRK2 from the cytoplasm to the membrane and stimulates process outgrowth. We are using systems biology approaches, including context likelihood of relatedness (CLR) and mode-of-action by network identification (MNI), to identify the LRRK2 regulatory network. Through this work we have developed a systems network regulatory map for LRRK2 action, and are currently identifying which of the pathways modulate the neurodegenerative pathways associated with Parkinson’s disease.
Dusonchet, J., Li, H., Guillily, M., Stafa, K., Pyenson, N., Liu, M., Derada, C., Glauser, L., Mamais, A., Citro, A., Saha, S., Liu-Yesucevitz, L., Schneider, B.L., Aebischer, P., Yue, Z., Bandopadhyay, R., Glicksman, M., Moore, D.J., Collins, J. J., Wolozin, B., A Parkinson’s disease gene regulatory network identifies RGS2 as a modulator of LRRK2 activity. Human Mol. Genetics. 2014 (EPub, PMID: 24794857).
Liu-Yesucevitz, L., Lin, A, L, Xu, Y, Kobrin, A, Petrucelli, L and Wolozin, B. ALS-linked mutations cause dysfunction of TDP-43-enriched RNA granules J. Neuroscience 34:4167-74 (2014). PMID: 24647938.
Boyd, J.D., Lee, P., Feiler, M.S., Zauur, N., Liu, M., Concannon, J., Ebata, A., Wolozin, B.*, Glicksman, M.A.* A high content screen identifies novel compounds that inhibit stress-induced TDP-43 cellular aggregation and associated cytotoxicity. . J. Biomol. Screening. (2014) 19:44-56. *Co-senior authors. PMID: 24019256.
Ravid, K., Wolozin, B., The scientist’s pledge. Academic Medicine 88(6):743 (2013) PMID: 23708595.
Wolozin, B., Regulated protein aggregation: Stress granules and neurodegeneration. Mol. Neurodegen. 7(1):56 (2012). PMID: 23164372. (Epub).
Vanderweyde, T., Yu, H., Varnum, M., Liu-Yesucevitz, L., Citro, A., Ikezu, T., Duff, K., Wolozin, B., Contrasting Pathology of Stress Granule Proteins TIA-1 and G3BP in Tauopathies. J. Neurosci. 32:8270-83 (2012). PMCID: PMC3402380.
McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2012 Dec 2. [Epub ahead of print] PMID: 23208308
Di Domenico, FD, Sultana, R, Ferree, A, Smith, K., Barone, E., Perluigi, M., Coccia, R., Pierce, W., Cai, J., Mancuso, C., Squillace, R., Wiengele, M., Wolozin, B. and Butterfield, D.A., Redox Proteomics Analyses of the Influence of Co-expression of Wild Type or Mutated LRRK2 and Tau on C. elegans Protein Expression and Oxidative Modification: Relevance to Parkinson Disease. Antioxidants & Redox Signaling, 17(11)1490-506 (2012). PMC3448940.
Chan, D., Citro, A., Cordy, J.M., Shen, G.C., Wolozin, B. Rac1 Rescues Neurite Retraction Caused By G2019s Leucine-Rich Repeat Kinase 2 (LRRK2). J. Biol. Chem.; 286(18): 16140-9 (2011). PMCID: PMC3091223.
Liu-Yesucevitz, L., Bilgutay, A., Zhang, Y-Z., Mehta, T., Citro, A., Zaruur, N., McKee, A., Bowser, R., Sherman, M., Petrucelli, L. and Wolozin, B., Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue. Plos ONE 2010; (5(10). pii: e13250). PMCID: PMC2952586.
Hsu, CH, Chan, D, Greggio, E., Saha, S., Guillily, M.D., Ferree, A., Raghavan, K., Shen, GC, Segal, L., Ryu, H., Cookson, M. R., Wolozin, B., MKK6 binds and regulates expression of Parkinson’s disease-related protein LRRK2. J. Neurochem., 112(6):1593-604 (2010). PMCID: PMC2856721.
Saha, S., Guililly, M., Ferree, A., Lanceta, J., Chan, D., Ghosh, J., Segal, L., Raghavan, K., Hsu, C., Cordy, J., Kuwahara, T., Iwatsubo, T., Goldstein, L., Cookson, M, and Wolozin, B., LRRK2 modulates vulnerability to mitochondrial dysfunction in C. elegans J. Neurosci., 29:9210-8 (2009). PMCID: PMC3127548.
Solomon A, Kåreholt I, Ngandu T, Wolozin B, Macdonald SW, Winblad B, Nissinen A, Tuomilehto J, Soininen H, Kivipelto M. Serum total cholesterol, statins and cognition in non-demented elderly. Neurobiol Aging. 2007 Nov 15.
Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE. Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease. BMC Med. 2007 Jul 19;5:20.
Wolozin B, Bednar MM. Interventions for heart disease and their effects on Alzheimer’s disease. Neurol Res. 2006 Sep;28(6):630-6. Review.
Wolozin B, Manger J, Bryant R, Cordy J, Green RC, McKee A. Re-assessing the relationship between cholesterol, statins and Alzheimer’s disease. Acta Neurol Scand Suppl. 2006;185:63-70. Review.
Takashima A, Shimojo M, Wolozin B. The players on the gamma-secretase team. Nat Med. 2006 Jul;12(7):766-7; discussion 767.
Bednar MM, Lee TA, Wolozin B, Weiss KB. Coronary artery bypass grafting is not a risk factor for dementia or Alzheimer disease. Neurology. 2006 Jun 13;66(11):1785; author reply 1785.
Ved R, Saha S, Westlund B, Perier C, Burnam L, Sluder A, Hoener M, Rodrigues CM, Alfonso A, Steer C, Liu L, Przedborski S, Wolozin B. Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J Biol Chem. 2005 Dec 30;280(52):42655-68. Epub 2005 Oct 19.
Lee TA, Wolozin B, Weiss KB, Bednar MM (2005) Assessment of the emergence of Alzheimer’s disease following coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty. J Alzheimers Dis. 2005 Aug;7(4):319-24. [Abstract]
Ved R, Saha S, Westlund B, Perier C, Burnam LG, Sluder A, Hoener M, Rodrigues CM, Alfonso A, Steer C, Liu L, Przedborski S, Wolozin B (2005). Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha -synuclein, parkin and DJ-1 in C. elegans. J Biol Chem. 2005 Oct 19; [Epub ahead of print] [Abstract]
Poon HF, Frasier M, Shreve N, Calabrese V, Wolozin B, Butterfield DA. (2005) Mitochondrial associated metabolic proteins are selectively oxidized in A30P alpha-synuclein transgenic mice–a model of familial Parkinson’s disease. Neurobiol Dis. 2005 Apr;18(3):492-8. [ Abstract ]
Frasier M, Walzer M, McCarthy L, Magnuson D, Lee JM, Haas C, Kahle P, Wolozin B. (2005) Tau phosphorylation increases in symptomatic mice overexpressing A30P alpha-synuclein. Exp Neurol. 2005 Apr;192(2):274-87. [ Abstract ]
Snyder H, Wolozin B. (2004) Pathological proteins in Parkinson’s disease: focus on the proteasome. J Mol Neurosci. 2004;24(3):425-42. Review. [ Abstract ]
Snyder H, Mensah K, Hsu C, Hashimoto M, Surgucheva IG, Festoff B, Surguchov A, Masliah E, Matouschek A, Wolozin B. (2004) beta-Synuclein reduces proteasomal inhibition by alpha-synuclein but not gamma-synuclein. J Biol Chem. 2005 Mar 4;280(9):7562-9. Epub 2004 Dec 9. [ Abstract ]
Wolozin B. (2004) Cholesterol, statins and dementia. Curr Opin Lipidol. 2004 Dec;15(6):667-72. [ Abstract ]
Wolozin B. (2004) Apolipoprotein E receptor LR11: intersections between neurodegeneration and cholesterol metabolism. Arch Neurol. 2004 Aug;61(8):1178-80. No abstract available. [ Abstract ]
Wolozin B, Brown J 3rd, Theisler C, Silberman S. (2004) The cellular biochemistry of cholesterol and statins: insights into the pathophysiology and therapy of Alzheimer’s disease. CNS Drug Rev. 2004 Summer;10(2):127-46. Review. [ Abstract ]
Brown J 3rd, Theisler C, Silberman S, Magnuson D, Gottardi-Littell N, Lee JM, Yager D, Crowley J, Sambamurti K, Rahman MM, Reiss AB, Eckman CB, Wolozin B. (2004) Differential expression of cholesterol hydroxylases in Alzheimer’s disease. J Biol Chem. 2004 Aug 13;279(33):34674-81. Epub 2004 May 17. [ Abstract ]
Frasier M, Wolozin B. (2004) Following the leader: fibrillization of alpha-synuclein and tau. Exp Neurol. 2004 Jun;187(2):235-9. Review. No abstract available. [ Abstract ]
Ghanbari HA, Ghanbari K, Harris PL, Jones PK, Kubat Z, Castellani RJ, Wolozin BL, Smith MA, Perry G. (2004) Oxidative damage in cultured human olfactory neurons from Alzheimer’s disease patients. Aging Cell. 2004 Feb;3(1):41-4. [ Abstract ]
Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A, De Lucia M, McGowan E, Lewis J, Prihar G, Kim J, Dillmann WH, Browne SE, Hall A, Voellmy R, Tsuboi Y, Dawson TM, Wolozin B, Hardy J, Hutton M. (2004) CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet. 2004 Apr 1;13(7):703-14. Epub 2004 Feb 12. [ Abstract ]
Wolozin B. (2003) Cholesterol and the biology of Alzheimer’s disease. Neuron. 2003 Jan 8;41(1):7-10. [ Abstract ]
Choi P, Snyder H, Petrucelli L, Theisler C, Chong M, Zhang Y, Lim K, Chung KK, Kehoe K, D’Adamio L, Lee JM, Cochran E, Bowser R, Dawson TM, Wolozin B. (2003) SEPT5_v2 is a parkin-binding protein. Brain Res Mol Brain Res. 2003 Oct 7;117(2):179-89. [ Abstract ]
Perry G, Castellani RJ, Smith MA, Harris PL, Kubat Z, Ghanbari K, Jones PK, Cordone G, Tabaton M, Wolozin B, Ghanbari H. (2003) Oxidative damage in the olfactory system in Alzheimer’s disease. Acta Neuropathol (Berl). 2003 Dec;106(6):552-6. Epub 2003 Aug 29. [ Abstract ]
Pappolla MA, Bryant-Thomas TK, Herbert D, Pacheco J, Fabra Garcia M, Manjon M, Girones X, Henry TL, Matsubara E, Zambon D, Wolozin B, Sano M, Cruz-Sanchez FF, Thal LJ, Petanceska SS, Refolo LM. (2003) Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology. 2003 Jul 22;61(2):199-205. [ Abstract ]
Snyder H, Mensah K, Theisler C, Lee J, Matouschek A, Wolozin B. (2003) Aggregated and monomeric alpha-synuclein bind to the S6′ proteasomal protein and inhibit proteasomal function. J Biol Chem. 2003 Apr 4;278(14):11753-9. Epub 2003 Jan 24. [ Abstract ]
Wolozin B. (2003) Cyp46 (24S-cholesterol hydroxylase): a genetic risk factor for Alzheimer disease. Arch Neurol. 2003 Jan;60(1):16-8. Review. No abstract available. [ Abstract ]
Egashira N, Iwasaki K, Ishibashi M, Hatip-Al-Khatib I, Wolozin B, Mishima K, Irie K, Fujiwara M. (2002) Hypoxia enhances beta-amyloid-induced apoptosis in rat cultured hippocampal neurons. Jpn J Pharmacol. 2002 Dec;90(4):321-7. [ Abstract ]
Petrucelli L, O’Farrell C, Lockhart PJ, Baptista M, Kehoe K, Vink L, Choi P, Wolozin B, Farrer M, Hardy J, Cookson MR. (2002) Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron. 2002 Dec 19;36(6):1007-19. [ Abstract ]
Wolozin B. (2001) Peering into proteolysis with presenilins. J Alzheimers Dis. 2001 Apr;3(2):191-193. [ Abstract ]
Wolozin B. (2002) Cholesterol and Alzheimer’s disease. Biochem Soc Trans. 2002 Aug;30(4):525-9. Review. [ Abstract ]
Golts N, Snyder H, Frasier M, Theisler C, Choi P, Wolozin B. (2002) Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein. J Biol Chem. 2002 May 3;277(18):16116-23. Epub 2002 Feb 15. [ Abstract ]
Wolozin B, Golts N. (2002) Iron and Parkinson’s disease. Neuroscientist. 2002 Feb;8(1):22-32. Review. [ Abstract ]
Ahn BH, Rhim H, Kim SY, Sung YM, Lee MY, Choi JY, Wolozin B, Chang JS, Lee YH, Kwon TK, Chung KC, Yoon SH, Hahn SJ, Kim MS, Jo YH, Min do S. (2002) alpha-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells. J Biol Chem. 2002 Apr 5;277(14):12334-42. Epub 2002 Jan 30. [ Abstract ]
Choi P, Golts N, Snyder H, Chong M, Petrucelli L, Hardy J, Sparkman D, Cochran E, Lee JM, Wolozin B. (2001) Co-association of parkin and alpha-synuclein. Neuroreport. 2001 Sep 17;12(13):2839-43. [ Abstract ]
Palacino JJ, Murphy MP, Murayama O, Iwasaki K, Fujiwara M, Takashima A, Golde TE, Wolozin B. (2001) Presenilin 1 regulates beta-catenin-mediated transcription in a glycogen synthase kinase-3-independent fashion. J Biol Chem. 2001 Oct 19;276(42):38563-9. Epub 2001 Aug 14. [ Abstract ]
Wolozin B. (2001) A fluid connection: cholesterol and Abeta. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5371-3. No abstract available. [ Abstract ]
Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000 Oct;57(10):1439-43. [ Abstract ]
Choi P, Ostrerova-Golts N, Sparkman D, Cochran E, Lee JM, Wolozin B. (2000) Parkin is metabolized by the ubiquitin/proteosome system. Neuroreport. 2000 Aug 21;11(12):2635-8. [ Abstract ]
Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B. (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci. 2000 Aug 15;20(16):6048-54. [ Abstract ]
Wolozin B, Behl C. (2000) Mechanisms of neurodegenerative disorders: Part 2: control of cell death. Arch Neurol. 2000 Jun;57(6):801-4. Review. No abstract available. [ Abstract ]
Wolozin B, Behl C. (2000) Mechanisms of neurodegenerative disorders: Part 1: protein aggregates. Arch Neurol. 2000 Jun;57(6):793-6. Review. No abstract available. [ Abstract ]
Palacino JJ, Berechid BE, Alexander P, Eckman C, Younkin S, Nye JS, Wolozin B. (2000) Regulation of amyloid precursor protein processing by presenilin 1 (PS1) and PS2 in PS1 knockout cells. J Biol Chem. 2000 Jan 7;275(1):215-22. [ Abstract ]
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Lab Phone: 617-414-2654