Benjamin L. Wolozin, MD, PhD

Professor, Pharmacology & Experimental Therapeutics

Benjamin Wolozin
617.358.1995
72 E. Concord St Housman (R)

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

  • Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Division of Graduate Medical Sciences
  • Professor, Neurology, Boston University School of Medicine

Education

  • Albert Einstein College of Medicine, MD
  • Wesleyan University, BA

Publications

  • Published on 10/1/2018

    Wolozin B. Disrupted in Dementia. Biol Psychiatry. 2018 Oct 01; 84(7):474-475. PMID: 30176990.

    Read at: PubMed
  • Published on 8/1/2018

    Maziuk BF, Apicco DJ, Cruz AL, Jiang L, Ash PEA, da Rocha EL, Zhang C, Yu WH, Leszyk J, Abisambra JF, Li H, Wolozin B. RNA binding proteins co-localize with small tau inclusions in tauopathy. Acta Neuropathol Commun. 2018 Aug 01; 6(1):71. PMID: 30068389.

    Read at: PubMed
  • Published on 7/9/2018

    Ruan QT, Yazdani N, Beierle JA, Hixson KM, Hokenson KE, Apicco DJ, Luttik KP, Zheng K, Maziuk BF, Ash PEA, Szumlinski KK, Russek SJ, Wolozin B, Bryant CD. Changes in neuronal immunofluorescence in the C- versus N-terminal domains of hnRNP H following D1 dopamine receptor activation. Neurosci Lett. 2018 Sep 25; 684:109-114. PMID: 30003938.

    Read at: PubMed
  • Published on 6/13/2018

    Li D, Wang L, Maziuk BF, Yao X, Wolozin B, Cho YK. Directed evolution of a picomolar-affinity, high-specificity antibody targeting phosphorylated tau. J Biol Chem. 2018 Aug 03; 293(31):12081-12094. PMID: 29899114.

    Read at: PubMed
  • Published on 3/27/2018

    Boeynaems S, Alberti S, Fawzi NL, Mittag T, Polymenidou M, Rousseau F, Schymkowitz J, Shorter J, Wolozin B, Van Den Bosch L, Tompa P, Fuxreiter M. Protein Phase Separation: A New Phase in Cell Biology. Trends Cell Biol. 2018 Jun; 28(6):420-435. PMID: 29602697.

    Read at: PubMed
  • Published on 11/20/2017

    Apicco DJ, Ash PEA, Maziuk B, LeBlang C, Medalla M, Al Abdullatif A, Ferragud A, Botelho E, Ballance HI, Dhawan U, Boudeau S, Cruz AL, Kashy D, Wong A, Goldberg LR, Yazdani N, Zhang C, Ung CY, Tripodis Y, Kanaan NM, Ikezu T, Cottone P, Leszyk J, Li H, Luebke J, Bryant CD, Wolozin B. Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat Neurosci. 2018 Jan; 21(1):72-80. PMID: 29273772.

    Read at: PubMed
  • Published on 5/17/2017

    Wolozin B, Sotiropoulos I. Dendritic TAU-telidge. EBioMedicine. 2017 06; 20:3-4. PMID: 28529034.

    Read at: PubMed
  • Published on 5/5/2017

    Ash PEA, Stanford EA, Al Abdulatif A, Ramirez-Cardenas A, Ballance HI, Boudeau S, Jeh A, Murithi JM, Tripodis Y, Murphy GJ, Sherr DH, Wolozin B. Dioxins and related environmental contaminants increase TDP-43 levels. Mol Neurodegener. 2017 05 05; 12(1):35. PMID: 28476168.

    Read at: PubMed
  • Published on 4/15/2017

    Russo A, Scardigli R, La Regina F, Murray ME, Romano N, Dickson DW, Wolozin B, Cattaneo A, Ceci M. Increased cytoplasmic TDP-43 reduces global protein synthesis by interacting with RACK1 on polyribosomes. Hum Mol Genet. 2017 Apr 15; 26(8):1407-1418. PMID: 28158562.

    Read at: PubMed
  • Published on 4/4/2017

    Maziuk B, Ballance HI, Wolozin B. Dysregulation of RNA Binding Protein Aggregation in Neurodegenerative Disorders. Front Mol Neurosci. 2017; 10:89. PMID: 28420962.

    Read at: PubMed

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