Laboratory of Neurodegeneration
Welcome to the Laboratory of Neurodegeneration under the direction of Principal Investigator Benjamin Wolozin, M.D./Ph.D.
The research on Parkinson Disease focuses on genetic factors implicated in Parkinson’s disease, including LRRK2, Α-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 α-synuclein and LRRK2 enhance the sensitivity of dopaminergic neurons to mitochondrial dysfunction. One of the main goals of our laboratory is to identify targets for therapeutic intervention. To this end, we have generated a Regulatory Network for LRRK2 that identifies numerous proteins/genes that modify LRRK2 function; this work is currently being reviewed. Our work identifying LRRK2 binding proteins points to particular biochemical pathways mediating the actions of LRRK2. We have recently shown how GTPases can modify the function of LRRK2. We demonstrated that rac1 binds and regulates LRRK2. Over-expressing rac1 can overcome deficits in neurite extension caused by the G2019S mutation in LRRK2. We also 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 mTOR inhibitors, such as rapamycin and ridiforalimus, which stimulate the neuron to remove protein aggregates, and offer neuroprotection.
Amyotrophic Lateral Sclerosis
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. Our work focuses on the role of TDP-43 as a RNA binding protein, which are a class of proteins that regulate trafficking of mRNA in neurons insuring that the correct protein is made at the correct place in the neuron. RNA binding proteins have an unusual biochemical behavior because they undergo reversible aggregation. We hypothesize that TDP-43 normally functions to regulate RNA metabolism and RNA translation/protein synthesis, through formation of RNA protein complexes. However, stress, mutations in TDP-43 and/or mutations in TDP-43 accessory proteins, such as ataxin-2, can lead to excessive formation of RNA protein complexes, including RNA granules, stress granules and trafficking granules, interfering with protein translation and leading to neurodegeneration. Formation of cytoplasmic TDP-43 inclusions appears to be intimately linked to RNA metabolism, and specifically the biology of RNA granules. RNA granules are protein-mRNA aggregates that appear in synapses, in dendrites and in neuronal soma; they function as centers that regulate local protein translation and metabolism of RNA. The stress granule (SG) is a type of RNA granule that forms in response to many different types of stress. Studies from our laboratory, and other laboratories, show that TDP-43 inclusions in human brain (as well as in cell culture) co-localize with SGs, and that agents that inhibit SG formation also inhibit formation of TDP-43 inclusions. Our research shows an intimate link between the pathophysiology of TDP-43 and the mechanisms of disease in ALS. Our work indicates that TDP-43 can be induced to form inclusions in cell culture and that most TDP-43 inclusions co-localize with SGs. SGs are cytoplasmic RNA granules that consist of mixed protein – RNA complexes. Our work shows that increased TDP-43 inclusion formation is associated with accumulation of TDP-43 detergent insoluble complexes. TDP-43 associates with SG by interacting with SG proteins, such as TIA-1, via direct protein-protein interactions, as well as RNA-dependent interactions. The signaling pathway that regulates SGs formation also modulates TDP-43 inclusion formation.
Importantly, we observed that inclusion formation mediated by WT or mutant TDP-43 can be suppressed by treatment with translational inhibitors that suppress or reverse SG formation. This suggests novel routes of pharmacotherapy. Finally, using Sudan black to quench endogenous autofluorescence, we have shown that TDP-43 positive-inclusions in pathological CNS tissue co-localize with multiple protein markers of stress granules, including TIA-1 and eIF3. Although we do not know whether SG formation is the only process mediating pathophysiology of ALS, study of SGs clearly provides a valuable approach for investigating processes that are likely to be central to the pathophysiology of ALS. The putative relationship between TDP-43 and SG biology provides a novel approach for dispersing TDP-43 inclusions using physiological pathways that normally regulate this reversible process and, indeed, we are developing novel pharmaceuticals capable of reversing inclusions formed by TDP-43.
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. Using immunoprecipitation combined with mass spectrometry, we showed that tau contributes to the regulation of RNA metabolism. Tau regulates the proteins that interact with RNA binding proteins, such as TIA1. Phosphorylation and somatodendritic localization of tau (which are pathological hallmarks of disease) contribute to the translational stress response by promoting stress granule formation. The converse is also true: tau localizes to stress granules. Persistent stress granules increase tau stability and promote tau aggregation. This work suggests that stress granules can serve as a nidus for tau pathology.
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. Our work indicates that interventions directed at RNA binding proteins can protect against the tau mediated neurodegeneration. For instance, knockdown or deletion of TIA1 inhibits the toxicity of mutant tau protein. Since there are about 800 RNA binding proteins, the vast array of aggregating proteins provides multiple 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 the Alzheimer brain, but not in neurons exhibiting tau pathology. Thus, this new pathway provides novel approaches for disease therapy and novel disease biomarkers.
Pharmacoepidemiology: We are using 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. Previously, we demonstrated that use of statins is associated with a reduced incidence of dementia. We do this work by using large databases, such as the Veteran’s Affairs Database (about 5 million subjects), to study FDA approved medications. The large size of these population based databases allows analysis of medication use in a manner that is just not possible in the smaller cohorts classically used by epidemiologists in the field of dementia research. The reason is that the prevalence of use of many medications is insufficient to produce meaningful results in cohorts with less than 30,000 – 100,000 people. The large size of population based databases, such as those in the Veterans Affairs system, provides sufficient statistical power to analyze how the patterns of secondary disease (such as dementia among users of angiotensin receptor blockers) vary among subjects using these medications. Our studies of pharmacoepidemiology generate hypotheses that that spur cellular and molecular research investigations back to the laboratory to determine the putative mechanism through which the medications might exhibit their protection. For instance, this work has prompted extensive studies on the role of cholesterol in regulation of the metabolism of amyloid precursor protein and production of β-amyloid. Cellular and Molecular Biology: Our current research related to Alzheimer’s disease focuses on the pathophysiology of RNA binding proteins and the protein translational system in Alzheimer’s disease. This is a rapidly evolving field that has received relatively scant attention, yet have a profound impact on the cell. Cellular stress elicits a switch in protein translation from cap-dependent to cap-independent RNA translation, which inhibits synthesis of non-housekeeping proteins, and maintains synthesis of proteins that protect against stress, such as heat shock proteins. The translational stress switch is associated with cytoplasmic translocation of mRNA binding proteins, and consolidation of these proteins with mRNA to form RNA protein complexes that are termed the stress granules (SGs). SGs function in part to triage RNA and sequester transcripts not needed for coping with the stress. The mechanism of SG formation is striking because it results from the regulated, reversible aggregation process of mRNA binding proteins, which is mediated by a polyglutamine rich prion-like domain. Recent studies suggest that stress granules are a form of pathology associated with neurodegenerative diseases. Studies of Huntington’s disease, Creutzfeld-Jacob disease and our recent study of ALS and frontotemporal dementia (FTLD-U) all exhibit inclusions composed of the pathological protein aggregate that are co-localized with TIA-1, a marker of SGs. However, the evolution of SG pathology in these diseases is uncharacterized. Our current work examines human cases with AD and a transgenic mouse model of tauopathy and Alzheimer’s disease to determine the development of SG pathology in these common diseases. Our results indicate that TIA-1-positive SGs are abundant in cases of AD and increase with disease severity in the JNPL3 mutant tau mouse. Co-localization of tau with TIA-1 SGs varies with disease severity. Pathological tau and SGs occur in separate compartments when present as small inclusions (1-3 μm), but co-localization increases dramatically with disease severity and SG size. In contrast, cytoplasmic SGs composed of TTP and G3BP show a pathological profile that is strikingly different that TIA-1 because G3BP become widely distributed as disease severity progresses, yet G3BP does not co-localize with tau inclusions at all, and TTP co-localizes only late in the disease process. The presence of RNA granules that accumulate in tauopathies, but are not co-localized with tau pathology, points to novel types of molecular neuropathology that is not associated with classic markers of disease pathology.
PhD Biomolecular Pharmacology/Biomedical Neuroscience
PhD Biomolecular Pharmacology
Research Assistant and Lab Technician
Former Postdoctoral Fellow
To view the Laboratory of Neurodegeneration’s PubMed publications, please click here.
Wolozin, B.L.: Towards an understanding of beta-lactamase catalysis. Undergraduate Thesis, 1980.
Wolozin, B.L., and Pasternak, G.W.: Classification of multiple morphine and enkephalin binding sites in the central nervous system. PNAS78(10):6181-6185, 1981.
Wolozin, B.L., Nishimura, S., and Pasternak, G.W.: The binding of Kappa and Sigma Opiates in rat brain. J. Neuroscience 2(6): 708-713, 1982.
Wolozin, B.L., Myerowitz, R., and Pratt, R.F.: Specific chemical modification of the readily nitrated tyrosine of the RTEM beta-lactamase and of bacillus cereus beta-lactamise I. The role of tyrosine in beta-lactamase catalysis. Biochem. Biophysics Acta 701(2):153-163, 1982.
Wolozin, B.L., Pruchnicki, A., Dickson, D.W., and Davies, P.: A neuronal antigen in the brains of Alzheimer patients. Science232:648-650, 1986.
Wolozin, B.L., and Davies, P.: Recent advances in the neurochemistry of Alzheimer’s Disease. J. Clin. Psychiatry. 48:23-30, 1987.
Wolozin, B.L., and Davies, P.: Alzheimer related neuronal protein A68: specificity and distribution. Ann. Neurol. 22:521-526, 1987.
Davies, P., Scicutella, A., and Wolozin, B.L.: A new protein in Alzheimer’s Disease. Branberry Reports 27:459-471, 1987.
Wolozin, B.L.: A neuronal antigen in the brains of Alzheimer patients. Graduate Dissertation, 1987.
Wolozin, B.L., Scicutella, A., and Davies, P.: Re-expression of a developmentally regulated antigen in Down Syndrome and Alzheimer’s Disease. PNAS 85:6202-6206, 1988.
Hyman, B.T., Van Hoesen, G.W., Wolozin, B.L., Davies, P., and Damasio, A.R.: Alz-50 antibody recognizes Alzheimer-related neuronal changes. Ann. Neurol. 27:371-379, 1988.
Wolozin, B.L.: Immunochemical approaches to the diagnosis of Alzheimer’s Disease. In: Becker, R.E., and Giacobini, E. (Eds.) Alzheimer’s Disease. Current Research in Early Diagnosis, Taylor and Francis, New York: 1990;
Lesch, K.P., Aulakh, C.S., Tolliver, T.J., Hill, J.L., Wolozin, B.L., and Murphy, D.L.: Differential effects of long-term lithium and carbamazepine administration on Gs_ and Gi_ protein in rat brain. Eur. J. Pharmacol. 207:355-359, 1991.
Wolozin, B.L., Sunderland, T., Zheng, B.B., Resau, J., Dufy, B., Barker, J., Swerdlow, R.D., and Coon, H.: Continuous culture of neuroblasts from adult human olfactory epithelium. J. Mol. Neuroscience 3:137-146, 1992.
Wolozin, B.L., Bacic, M., Merrill, M.J., Lesch, K.P., Chen, C., Lebovics, R.S., and Sunderland, T.: Differential expression of carboxyl terminal derivatives of amyloid precursor protein among cell lines. J. Neurosci. Res. 33:163-169, 1992
Wolozin, B.L., Chung, D., Zheng, B.B., Lesch, K.P., Lebovics, R.S., and Sunderland, T.: The β/A4 domain of APP: Antigenic differences between cell lines. J. Neurosci. Res. 33:189-197, 1992.
Lesch, K.P., Hough, C.J., Aulakh, C.S., Wolozin, B.L., Tolliver, T.J., Hill, J.L., Chuang,D.M., and Murphy, D.L.: Fluoxetine modulated G protein ss , qq and a12 subunit mRNA expressed in rat brain. Eur. J. Pharmacol. 227:233-237, 1992.
Lesch, K.P., Aulakh, C.S., Wolozin, B.L., Tolliver, T.J., Hill, J.L., and Murphy, D.L.: 3-(2-Carboxypiperazin-4-yl)Propyl-1-phosphonic acid decreases NMDA receptor mRNA. Eur. J. Pharmacol. 227:109-111, 1992.
Lesch, K.P., Aulakh, C.S., Wolozin, B.L., and Murphy, D.L.: Serotonin (5-HT) receptor, 5-HT transporter and protein-effector expression: Implications for depression. Pharmacol. Toxicol. 71:49-60, 1992.
Lesch, K.P., Aulakh, C.S., Wolozin, B.L., Tolliver, T.J., Hill, J.L., and Murphy, D.L.: Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants. Mol. Brain Res. 17:31-35, 1993.
Wolozin, B.L., Lesch, K.P., Lebovics, R.S., and Sunderland, T.: Olfactory neuroblasts from Alzheimer donors: Studies on APP processing and cell regulation. Biol. Psychiatry. 34:824-838, 1993.
Lesch, K.P., Wolozin, B.L., Estler, H.C., Murphy, D.L., and Riederer, P.: Isolation of a cDNA encoding the human brain serotonin transporter.J. Neural Transm. 91: 67-72, 1993.
Lesch, K.P., Aulakh, C.S., Wolozin, B.L., Riederer, P., Hill, J.L., and Murphy, D.L.: Norepinephrine, serotonin and vesicular monoamine transporter in depression and bipolar disorder: Expression during long-term antidepressant treatment. Neuropsychopharmacology9:34S-35S, 1993.
Wolozin, B.L.: The processing of amyloid precursor protein. Foundation Ipsen: Alzheimer Actualities 7:6-8, 1993.
Lesch, K.P., Gross, J., Wolozin, B.L., Murphy, D.L., and Riederer, P.: Extensive sequence divergence between the human and rat brain vesicular monoamine transporter: Possible molecular basis for species differences in the susceptibility to MPP+. J. Neural Transm. 93:75-82, 1993.
Lesch, K.P., Wolozin, B.L., Murphy, D.L., and Reiderer, P.: Primary structure of the human platelet serotonin uptake site: Identity with the brain serotonin transporter. J. Neurochem. 60:2319-2322, 1993.
Johnson, G., Brane, D., Basaric-Keys, J., Lebovics, R.S., Merril, C.R., Sunderland, T., and Wolozin, B.L.: Protein alterations inolfactory neuroblasts from Alzheimer donors. Neurobiol. Aging 15:675-680, 1994.
Lesch, K.-P., Balling, U., Gross, J., Strauss, K., Wolozin, B.L., Murphy, D.L., and Riederer, P.: Organization of the human serotonin transporter gene. J. Neural Transm. 95: 157-162, 1994.
Lesch, K.P., Gross, J., Wolozin, B.L., Franzek, E., Riederer, P., Murphy, D.L., Direct Sequencing of the reserpine-sensitive vesicular monoamine transporter complementary DNA in unipolar depression and manic-depressive illness. Psychiatric Genetics 4: 153-90 (1994).
Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., Guido, T., Hagopian, S., Johnson‑Wood, K., Khan, K., Lee, M., Leibowitz, P., Lieberburg, I., Little, S., Masliah, E., McConlogue, L., Montoya-Zavala, M., Mucke, L., Paganini, L., Penniman, E., Power, M., Schenk, D., Seubert, P., Snyder, B., Soriano, F., Tan, Hua., Vitale, J., Wadsworth, S.,Wolozin, B., and Zhao, J.: Development of neuropathology similar to Alzheimer’s Disease in transgenic mice overexpressing the 717 V-F β-amyloid precursor protein. Nature, 373: 523-8, 1995.
Luo, Y Q. , Hirashima, N., Li, Y.H., Alkon, D.L., Sunderland, T., Etcheberrigaray, R., and Wolozin, B.L.: Physiological levels of b-amyloid increase tyrosine phosphorylation and cytosolic calcium. Brain Res., 681: 65-74 (1995).
Wolozin,B., Hirashima, N., Luo, Y.,Li, Y.H., Alkon, D.L., Etcheberrigaray, R. and Sunderland, T., Transforming growth factor induces a responsive calcium fluxes in neurons. NeuroReport, 6: 1301-5 (1995).
Lesch, K.P., Franzek, E., Gross, J., Wolozin, B.L., Riederer, P., and Murphy, D.L.: Primary Structure of the Serotonin transporter in unipolar and bipolar disorder. Biol. Psychiatry. 37: 215-23 (1995).
Iwasaki, K., Sunderland, T., Kusiak, J.W. and Wolozin, B., Changes in gene transcription during a_-mediated cell death. Mol. Psych. 1:65-71 (1996).
Wolozin, B., Luo, Y., and Wood, K.: Neuronal Loss and Aging in Cellular Aging and Cell Death, Eds. N.J. Holbrook, G.R. Martin and R. A. Lockshin (John Wiley & Sons, Inc., NY) 283-302.
Wolozin, B.L., Basaric-Keys, J., Canter, R., VanderPutten, D., and Sunderland, T.: Differential regulation of APP by apolipoprotein E3 and E4. Ann. NY Acad. Sci. 777:322-6 (1996).
Wolozin, B., Basaric-Keys, J., Canter, R., Li, Y., Strickland, D and Sunderland, T., Differential regulation of APP secretion by apolipoprotein E3 and E4, Neurodegenerative Diseases ‘95: Molecular and Cellular Mechanisms. Ed. G. Fiskum (Plenum, Press, NY) 97-102.
Luo, Y., Sunderland, T. and Wolozin, B., Physiologic Levels of b-Amyloid Activate PI3-Kinase with the Involvement of Tyrosine Phosphorylation. J. Neurochem. 67:978-987 (1996).
Vawter, M.P., Basaric-Keys, J., Li, Y., Lebovics, R.S., Lesch, K.P., Kulaga, H., Freed, W.J., Sunderland, T., Wolozin, B., Human olfactory neuroepithelial cells: Tyrosine phosphorylation and process extension are increased by the combination of IL1_, IL6, NGF and βFGF. Exp. Neurol.. 142:179-194, 1996.
Vito, P., Wolozin, B, Ganji, K, Iwasaki, K., Lacana, E. and D’Adamio, L. Requirement of the familial Alzheimer’s Disease gene PS-2 for apoptosis. J. Biol. Chem. 271:31025-31028, 1996.
Wolozin, B., Iwasaki, K, Vito, P., Sunderland, T., Ganji, K., Lacana, E., Zhao, B., Kusiak, J., Wasco, W. and D’Adamio, L. Participation of Presenilin-2 in apoptosis: Enhanced basal activity conferred by Alzheimer mutation. Science. 274:1710-1713, 1996.
Wolozin, B. Redoubling our effort in redox chemistry. Mol. Psych.1:352-355, 1996.
Luo, Y., Sunderland, T., Roth, G.S. and Wolozin, B. Physiological levels of _-amyloid peptide promote PC12 cell proliferation. Neurosci. Lett. 217:125-128, 1996.
Wolozin, B. ICE and apoptosis. Mol. Psych. 2:184-187, 1997.
Goldstein, B.J., Wolozin, B.L., Schwob, J.E. FGF2 supresses neuronogenesis of a cell line derived from rat olfactory epithelium. J. Neurobiol. 33:411-8, 1997.
Luo, Y., Hawver, D. B., Iwasaki, K., Sunderland, T., Roth, G. S. andWolozin, B. Physiological levels of ß‑amyloid peptide stimulate protein kinase C in PC12 cells. Brain Res. 769:287-95, 1997.
Wallace., W, Akar, C., Lyons, W.E., Kole, W.E., Egan, J., Wolozin, B., Amyloid precursor protein requires the insulin signaling pathway for neurotrophic activity. Molecular Brain Research 52: 213-227, 1997.
Wolozin, B., Alexander, P., Palacino, J. Regulation of apoptosis by presenilins. Neurobiol. Aging. 19 (1S): S23-7, 1998.
Takashima, A., Murayama, M., Murayama, O., Kohno, T., Honda, T., Yasutake, K., Nihonmatsu, N., Mercken, M., Yamaguchi, H., Sugihara, S., Wolozin, B. Presenilin 1 Associates with Glycogen Synthase Kinase-3b, Proc. Natl. Acad. Sci., USA. 95:9637-41, 1998.
Murayama M; Tanaka S; Palacino J; Murayama O; Honda T; Sun X; Yasutake K; Nihonmatsu N; Wolozin B; Takashima A. Direct association of presenilin-1 with beta-catenin. FEBS Lett 14: 433:73-7, 1998.
Wolozin, B., Jones, C., Maheshwari, S., Dukoff, R., Nagula, S., Shulman, N.R. and Sunderland, T., Physiologic levels of ß-amyloid augment platelet aggregation: Reduced activity of familial angiopathy-assoicated mutants. Mol. Psych. 3: 500-507, 1998
Wolozin, B. and Palacino, J., Presenilins and their role in apoptosis. In eds. C. Haass, The Molecular Biology of Alzheimer’s Disease. Harwood Academic Publishers, Australia. 1998. pp. 247-76
Abrams, MT, Kaufmann, WE, Rousseau, F, Oostra, BA, Wolozin, B, Taylor, CV, Lishaa, N, Morel, ML, Hoogenveen, A, Reiss, AL. FMR1 gene expression in olfactory neuroblasts from two males with fragile X syndrome. Am. J. Med. Gen. 82: 25-30, 1999.
Wolozin, B. Genes in Alzheimer’s Disease, in “Genes, Behaviour and Health”, (Advisory Committee on Health Research of the World Health Organization, Geneva, Switzerland). pp. 123-144, 1999.
Ostrerova, N., Petrucelli, L., Farrer, M., Mehta, N., Palacino, J., Hardy, J. and Wolozin, B. _-Synuclein shares physical and functional homology with 14-3-3 proteins. J. Neurosci. 19: 5782-91, 1999.
Sunderland T; Wolozin B; Galasko, D., Levy, J., Dukoff, R., Bahro, M., Lasser, R., Motter, R., Lehtimaki, T., Seubert, P., Longitudinal stability of CSF tau levels in Alzheimer patients. Biol. Psych. 46:750-5, 1999.
Palacino, J., Berechid, B., C. Eckman, S. Younkin, Alexander, P., Nye, J.,Wolozin, B. Regulation of APP processing by Presenilin 1 and 2 in Presenilin 1 knockout cells. J. Biol. Chem. 275: 215-222, 2000.
Wolozin, B. and Behl, C., Mechanisms of neurodegenerative disorders. Part A: Protein Aggregates. Arch. Neurol. 57: 793-6, 2000
Wolozin, B. and Behl, C., Mechanisms of neurodegenerative disorders. Part B: Control of cell death. Arch. Neurol. 57: 797-800, 2000
Ostrerova-Golts, N., Petrucelli, L., Hardy, J., Lee, J.M., Farer, M.,Wolozin, B., The A53T α-Synuclein Mutation Increases Iron-Dependent Aggregation and Toxicity. J. Neurosci. 20: 6048-54, 2000.
Choi, P., Ostrerova-Golts, N., Sparkman, D., Cochran, E., Lee, J.M.,Wolozin, B., Parkin is Metabolized by the Ubiquitin/Proteosome System, NeuroReport 11: 2635 – 9, 2000.
*Wolozin, B.L., Kellman, W., Ruosseau, P., Celesia, G.G. and Siegel, G., Decreased Prevalence of Alzheimer’s Disease, Associated with HMG-CoA Reductase Inhibitors. Archives Neurol., 57: 1439 – 1443, 2000. *Reviewed in the Editors Choice column of Science, 290: 1857 (2000), and discussed in Science, 294: 506-7 (2001).
Wolozin, B., A fluid connection: Cholesterol and Ab, (Invited Commentary) PNAS 98:5371-3 (2001).
Wolozin, B., Peering into proteolylsis with presenilins, (Invited Commentary) Journal Alz. Dis. 3: 191-3 (2001).
Wolozin, B., Golts, N., Choi, P., Frasier, M., Snyder, H. and Palacino, J., Looking beyond b-amyloid: a-Synuclein and Neurodegeneration. Research and Practice in Alzheimer’s disease, Vol. 4, 2001.
Choi, P., Golts, N., Snyder, H., Petrucelli, L., Chong, M., Hardy, J.,Sparkman, D., Cochran, E., Lee, J.M., Wolozin, B., Co-association of parkin and α-synuclein, NeuroReport. 12: 2839-45 (2001).
Palacino, J.J., Murphy, M.P., Murayama, O., Iwasaki, K., Fujiwara, M., Takashima, A., Golde, T.E., Wolozin, B., Presenilin 1 Regulates β-Catenin-Mediated Transcription in a GSK 3b-Independent Fashion JBC 276(42):38563-38569 (2001).
Ahn, B. H., Rhim, H., Kim, S. Y., Sung, Y. M., Lee, M. Y., Choi, J. Y.,Wolozin, B., Chang, J. S., Lee, Y. H., Kwon, T. K., Chung, K. C., Yoon, S. H., Hahn, S. J., Kim, M. S., Jo, Y. H., and Min, D. S. Alpha-synuclein interacts with phospholipase D isozymes and inhibits pervanadate induced phospholipase D activation in human embryonic kidney 293 cells. J Biol Chem. 277(14):12334-42 (2002).
Wolozin, B. and Siegel, G., Response to letter: Statins and Dementia. Archives Neurol. 58: 1169 (2001).
Wolozin, B. and Siegel, G., Response to Letter: Statin-Alzheimer Disease Association Not Yet Proven. Archives Neurol. 58: 1022 (2001).
Wolozin, B. and Siegel, G., Response to Letter: Statin Therapy and the Prevention of Dementia. Archives Neurol. 58: 1023 (2001)
Wolozin, B. and Golts, N., Synuclein, iron and Parkinson’s disease, The Neuroscientist. 8(1): 22-32 (2002).
Golts, N., Snyder, H., Frasier, M., Theisler, C., Choi, P., Wolozin, B. Magnesium inhibits spontaneous and iron-induced aggregation of alpha –synuclein. J. Biol. Chem. 277:16116-23 (2002).
Wolozin, B., Cholesterol and Alzheimer’s disease. Biochemical Society Transactions 30(4): 525-30 (2002).
Petrucelli, L., O’Farrell, C., Kehoe, K., Vink, L., Lockhart, P.J., Baptista, M., Wolozin, B. Choi, P., Farrer, M., Hardy, J., Cookson, M.R., Parkin protects against the toxicity associated with over-expression of synuclein: Proteasome dysfunction selectively affects dopaminergic neurons. Neuron 36:1007-19 (2002).
Egashira N, Iwasaki K, Ishibashi M, Hatip-Al-Khatib I, Wolozin B, Mishima K, Irie K and Fujiwara M., Hypoxia Enhances beta-Amyloid-Induced Apoptosis in Rat Cultured Hippocampal Neurons. Japanese J Pharmacol 90:321-327 (2002).
Wolozin, B., Cyp46 (24-Cholesterol Hydroxylase): A genetic risk factor for Alzheimer’s Disease. Archives of Neurology 60:16-8 (2003) (invited commentary).
Snyder, H., Mensah, K., Theisler, C., Lee, J. M., Matouschek, A. andWolozin, B., Aggregated and Monomeric a-Synuclein bind to the S6’ Proteasomal Protein and Inhibit Proteasomal Function. J. Biol. Chem. 278:11753-9 2003.
Choi P., Snyder, H.,Petrucelli L., Theisler, C., Chong M., Zhang Y., Lim K., Chung K., Kehoe K., L. D’Adamio, Lee J.M., Cochran E., Bowser R., Dawson T., Wolozin, B., SEPT5 v2 is a parkin-binding protein. Mol. Brain Res. 117:179-189 (2003).
Perry G, Castellani RJ, Smith MA, Harris PL, Kubat Z, Ghanbari K, Jones PK, Cordone G, Tabaton M, Wolozin B, Ghanbari H., Oxidative damage in the olfactory system in Alzheimer’s disease. Acta Neuropathol (Berl). 106:552-6 (2003).
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. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology.61:199-205 (2003).
Wolozin, B. Cholesterol and the Biology of Alzheimer’s disease. Neuron 41:7010 (2004) (Invited Commentary).
Petrucelli, L., Dickson, D., Kehoe, K., Taylor, J., Snyder, H., Grover, A., McGowan, E., Lewis, J., Dillman, W., Browne, S.E., Voellmey, R., Tsuboi, Y., Dawson., T.M., Wolozin, B., Hardy, J., Hutton, M., CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Human Molecular Genetics 13:703-14 (2004).
Frasier, M., Wolozin, B., Following the leader: Fibrillization of a-synuclein and tau. Exp. Neurol. 187:235-9 (2004) (Invited Commentary).
Wolozin, B., Apo E Receptor LR11: Intersections between Neurodegeneration and Cholesterol Metabolism. Arch. Neurol. 61:1178-80 (2004) (Invited commentary).
Wolozin, B., Brown, J., Theisler, C., Silberman, S., The Cellular Biochemistry of Cholesterol and Statins: Insights into the Pathophysiology and Therapy of Alzheimer’s Disease. CNS Drug Reviews 10:127-46 (2004).
Ghanbari HA, Ghanbari K, Harris PL, Jones PK, Kubat Z, Castellani RJ, Wolozin BL, Smith MA, Perry G., Oxidative damage in cultured human olfactory neurons from Alzheimer’s disease patients. Aging Cell. 3:41-4 (2004).
Brown, J., Theisler, C., Silberman, S., Magnuson, D., Russell, D.W., Marquez-Sterling, N., Lee, J.M., Yager, D., Crowley, J., Sambamurti, K., Rahman, M., Reiss, A.B., Eckman, C.B., Wolozin, B., Differential Expression of Cholesterol Hydroxylases in Alzheimer’s disease. JBC 279:34674-81 (2004).
Frasier, M., Walzer, M., McCarthy, L., Magnuson, D., Lee, J.M., Haas, C., Kahle, P. and Wolozin, B., Tau phosphorylation increases in symptomatic mice over-expressing A30P α-synuclein. Exp. Neurol, 192:274-87 (2005).
Poon, H.F., Frasier, M., Kahle, P., Haass, C., Sherve, N., Calabrese, V., Wolozin, B., Butterfield, D.A. Mitochondrial associated Metabolic Proteins are Selectively Oxidized in A30P a-Synuclein Transgenic Mice – A Model of Familial Parkinson’s Disease. Neurobio. Dis., 18:492-8 (2005).
Snyder, H., Mensah, K., Hashimoto, M., Surgucheva, I.G., Festoff, B., Surguchov, A., Masliah, E., Matouschek, A., Wolozin, B. β-Synuclein Reduces Proteasomal Inhibition by a-Synuclein but not g-Synuclein. JBC 280:7562-9 (2005).
Snyder, H., Wolozin, B., Pathological proteins in Parkinson’s disease: focus on the proteasome. J Mol Neurosci. 24:425-42 (2005).
Lee, TA Wolozin*, B, Weiss, K, Bednar, MM, Assessment of the Emergence of Alzheimer’s Disease Following Coronary Artery Bypass Graft Surgery or Percutaneous Transluminal Coronary Angioplasty. J. Alzheimer’s Disease 7:319-24 (2005) (*Corresponding Author).
Ved, R., Saha, S., Sluder, A., Westlund, B., Burnam, L., Hoener, M., Przedborsky, S., Alfonso, A., Liu, L., Wolozin, B. Similar Patterns of Mitochondrial Vulnerability and Rescue Induced by Genetic Modification of a-Synuclein, Parkin and DJ-1 in C. Elegans. JBC, 280(52):42655-68 (2005).
Wolozin, B., J. Manger, R. Bryant, J. Cordy, R.C.Green and A. McKee. Cholesterol, Alzheimer’s disease and Statins: Re-assessing the relationship between cholesterol, statins and Alzheimer’s disease. Acta Neuropathologica Suppl. 185:63-70 (2006).
Frasier, M., Frausto, S., Lewicki, D., Golbe, L., Wolozin, B., DJ-1 Expression Increases in Mice Over-Expressing A30P a-Synuclein. In ALZHEIMER’S AND PARKINSON’S DISEASES: INSIGHTS,PROGRESS AND PERSPECTIVES (Eds., Hanin and Fisher, Springer, NY) (2008).
Wolozin, H and Wolozin, B., The Unconscious in Economic Decision-Making: Convergent Voices. Journal of Socio-Economics (in press, 2006).
Wolozin, B., Interpreting Clinical Studies of Putative Therapeutics for Alzheimer’s disease. In, ed. Cuello, C., Pharmacological and Mechanisms in Alzheimer’s Therapeutics (Springer, NY, 2006).
Wolozin, B. and Bednar, M. M., Interventions for Heart Disease and Their Effects on Alzheimer’s disease, In, ed., de la Torre, J. C., Impact of Heart Disease and Stroke on Alzheimer’s Disease, Neurologic Research 28:630 – 6 (2006).
Wolozin, B., Cholesterol, Statins and Alzheimer’s disease: Past, Present and Future, In, ed. Sun, M. K., Research Progress in Alzheimer’s Disease and Dementia (2006).
Takashima A, Shimojo M, Wolozin B. The players on the gamma-secretase team. Nat Med. Jul;12(7):766-767 (2006).
Bednar M.M., Lee TA, Wolozin B, Weiss K.B.. Coronary artery bypass grafting is not a risk factor for dementia or Alzheimer disease. Neurology. Jun 13;66(11):1785 (2006).
Cordy, J.M. and Wolozin, B, Cholesterol and Alzheimer’s disease. In eds Barrow C.J., Small D.H.. Abeta Peptide and Alzheimer’s Disease: Celebrating a Century of Research. (London: Springer-Verlag, 2006, 312 pp).
Wolozin, B., Wang, SW, Lee, A, Lee TA, Kazis, LE, Use of simvastatin is associated with a reduction in the incidence of dementia and Parkinson’s disease. BMC Medicine 5:20 (2007). PMID: 17640385
Wolozin, B., Saha, S., Guillily, M., Ferree, A., Riley, M., Investigating Convergent Actions of Genes Linked to Familial Parkinson’s Disease. Neurodegenerative Diseases, 5:182-5 (2008). PMID: 18322385
Zerbinatti, CV, Cordy, JM, Chen, CD, Guillily, M, Suon, S, Ray, WJ, Seabrook, GR, Abraham, CR, Wolozin, B, Oxysterol-binding protein-1 (OSBP1) modulates processing and trafficking of the amyloid precursor protein. Mol. Neurodegen 3:5 (2008). PMID: 18348724
Tezapsidis N, Johnston JM, Smith MA, Ashford JW, Casadesus G, Robakis NK, Wolozin B, Perry G, Zhu X, Greco SJ, Sarkar S., Leptin: a novel therapeutic strategy for Alzheimer’s disease. J. Alz. Dis. 29:731-40 (2009). PMID: 19387109
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. 30: 1006-9 (2009).
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, MR, and Wolozin, B., LRRK2 modulates vulnerability to mitochondrial dysfunction in C. elegans J. Neurosci, 29:9210-8 (2009). PMID: 19625511
Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA., Midlife Serum Cholesterol and Increased Risk of Alzheimer’s and Vascular Dementia Three Decades Later. Dementia Geriatric Cogn. Disord. 28:75-80 (2009). PMID: 19648749
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). PMID: 20067578
Hsu, CH, Chan, D. and Wolozin, B., LRRK2 and the stress response: Interaction with MKK and JNK interacting proteins, Neurodegen. Dis. 7(1-3):68-75 (2010). PMID: 20173330
*Li, N.C., Lee, A., Whitmer, R. A., Kivipelto, M., Lawler, E., Kazis, L.E. and Wolozin, B., Use of Angiotensin Receptor Blockers and the Risk of Dementia in a Predominantly Male Population: A Prospective Cohort Analysis. BMJ 340:b5465 doi: 10.1136/bmj.b5465 (2010). PMID: 20068258 * Commentary on the manuscript in the same issue of BMJ.
Liu-Yesucevitz, L., Bilgutay, A., Zhang, Y-Z., Mehta, T., Citro, A., Zaruur, N., McKee, A., Bowser, R., Sherman, M., Petrucelli, L. andWolozin, B., Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue. Plos ONE (5(10). pii: e13250), (2010) PMID: 20948999.
Kumar, A., Greggio, E., Beilina, A., Kaganovich, A., Chan, D., Taymans, J.M., Wolozin, B., Cookson, M.R., The Parkinson’s disease associated LRRK2 exhibits weaker in vitro phosphorylation of 4E-BP compared to autophosphorylation. Plos ONE 15(1):E8730 (2010). PMID: 20090955
Carballo-Carbajal, I., Weber-Endress, S.U.K., Klein, C., Patenge, N., Rovelli, G., Wolozin, B., Gasser, T. and Kahle P.J., Leucine-rich repeat kinase 2 induces a-synuclein expression via the extracellular signal regulated kinase pathway. Cell Signaling 22(5):821-7 (2010). PMID: 20074637
Solomon A,Sippola R,Soininen H,Wolozin B,Tuomilehto J,Laatikainen T, Kivipelto M., Lipid-lowering treatment is related to decreased risk of dementia: a population-based study (FINRISK), 7(1-3):180-2 (2010). PMID: 20224281
Vanderweyde T, Bednar MM, Forman SA and Wolozin B, Iatrogenic risk factors for Alzheimer’s disease: Surgery and Anesthesia. Journal of Alzheimer’s Disease. (2010) Epub. PMID: 20858967
Wolozin, B. , Lee, A., Li, N.C., Kazis, L.E., Pharmaco-epidemiological Studies Using the Veterans Affairs Health System Decision Support System Database, in Efficient Decision Support Systems: Practice and Challenges – From Current to Future / Book 3 (2011)(ISBN 978-953-308-63-9). Intechweb.org
Devine MJ, Kaganovich A, Ryten M, Mamais A, Trabzuni D, Manzoni C, McGoldrick P, Chan D, Dillman A, Zerle J, Horan S, Taanman JW, Hardy J, Marti-Masso JF, Healey D, Schapira AH, Wolozin B, Bandopadhyay R, Cookson MR, van der Brug MP, Lewis PA., Pathogenic LRRK2 Mutations Do Not Alter Gene Expression in Cell Model Systems or Human Brain Tissue. PLoS One. 2011;6(7):e22489. Epub 2011 Jul 22. PMID: 21799870.
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). PMID: 21454543.
Wolozin B, Gabel C, Ferree A, Guillily M, Ebata A., Watching worms whither: modeling neurodegeneration in C. elegans, Prog Mol Biol Transl Sci. 2011;100:499-514, PMID: 21377635.
Liu-Yesucevitz, L. Bassell, G.J., Gitler, A.D., Hart, A.C., Klann, E., Richter, J.D., Warren, S.T. and Wolozin, B., Local RNA Translation at the Synapse and in Disease. J. Neurosci. (in press).
- Alzforum: Reviews current research in Alzheimer’s disease, Parkinson’s disease and ALS
- Michael J. Fox Foundation: Current research in Parkinson’s disease
- The Alzheimer Association
- The Department of Pharmacology, Boston University:
- Boston University Alzheimer Center:
- Boston University Movement Disorders Center
- The Skeptical Inquirer
- Wolozin Lab Data Compendia (ID: “WolozinLab”, Password Required)
Benjamin Wolozin, M.D., Ph.D.
Departments of Pharmacology & Experimental Therapeutics and Neurology
Boston University School of Medicine
72 East Concord St., R614
Boston, MA 02118-2526