Benjamin Wolozin, M.D., Ph.D.
Professor of Pharmacology and Neurology
Department of Pharmacology
M.D., Ph.D.: Albert Einstein College of Medicine
Lab Page: Wolozin Laboratory
Pathophysiology of Neurodegeneration: Molecular and cellular Biology
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 recently demonstrated 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.
Amyotrophic Lateral Sclerosis (ALS): Our current work focuses on a protein, TDP-43, that was recently shown to be the predominant protein that accumulates in the cytoplasm of neurons during the course of the disease. TDP-43 is an RNA binding protein. 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. We are currently examining the molecular pathways regulating TDP-43 inclusion formation, and how mutations in TDP-43 modify RNA processing and protein translation.
Alzheimer disease: In our basic science research, we are examining the how the degeneration modifies RNA processes, protein translation and stress granule biology. In our epidemiological research we are working with Lewis Kazis (BU School of Public Health) and Rachel Whitmer (Kaiser Permanente Health System applying epidemiological approaches to identify promising drug candidates for therapy of Alzheimer’s disease. Our current work focuses on Angiotensin Receptor Blockers, which are associated with a strong reduction in the incidence and progression of dementia among patients with Alzheimer’s disease and possibly also Parkinson’s disease. We use large databases, such as the Veteran’s Affairs Database (~5 million subjects), to study FDA approved medications, and then translate the findings back to the laboratory to determine the putative mechanism through which the medications might exhibit their protection.
Neuroprotection: We examine a range of novel compounds that modulate neuroprotective pathways. We are developing novel compounds to inhibit the aggregation of TDP-43, based on lead compounds from a high throughput screen of a 158,000 compound chemical library. We also examine novel compounds targeting known neuroprotective pathways. Compounds that we are studying, or have studied include: Sirt1 agonists (such as resveratrol, the compound found in red wine or SRT1720, produced by Sirtris Pharmaceuticals), and stimulators of autophagy (such as ridiforalimus and rapamycin).
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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