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Garth Hall

Garth Hall
Garth F. HallAssociate Professor
  • CollegeCollege of Sciences
  • DepartmentBiological Science
  • Phone(978) 934-2893
  • EmailGarth_Hall@uml.edu

Research Interests

My main long term research focus has been on the generation and maintenance of neuronal form, and related aspects of neuronal cell biology. In particular, I am interested in how neurons generate and maintain cellular polarity and the role that neuronal polarity disruption may play in a) the recovery of axonal function after axotomy and the cytopathogenesis of AlzheimerÍs disease and related conditions. In recent years, I have focused on the role played by the cytoskeleton-associated protein tau in neurodegenerative tauopathies, and have become increasingly interested in the possible role of tau abnormalities in mediating interneuronal aspects of these diseases. This has led to current interests in tau-NF interactions and synergistic interactions between tau, PrP and alpha synuclein and their possible involvement in endocytosis/secretion of tau in AD. My current interests are outgrowths of my thesis research with Dr. Melvin Cohen at Yale in the 1980s, where I discovered and characterized axotomy-induced neuronal polarity loss in a subset of giant Muller neurons (ABCs) in the hindbrain of the ammocoete sea lamprey1-5. I became interested in the possibility that axonal degeneration6 and polarity loss7-8 might be central events in the pathogenesis of AlzheimerÍs Disease9, and took a postdoctoral position with Dr. Kosik, with whom I used the ABC axotomy model to study the interaction of axotomy and endogenous cytoskeletal elements10-13. I have since maintained my interest in the cellular response to axotomy, with a particular interest in the role of neurofilaments in maintaining axonal form14-18. However, my major research focus has since been on the role of the cytoskeleton in disease pathogenesis as described below. I have used the lamprey ABC system as a model to study the cytopathology of human tau since 1994, and published a study of neurodegeneration induced by tau overexpression via plasmid injection into ABCs in 199719. This was the first study to demonstrate tau-induced cytotoxicity in any system, and its success (following years of unsuccessful attempts to model tau-induced degeneration in cell culture) highlighted the need for in situ modeling approaches to tauopathy. In 1997 I moved to U. Mass. Lowell and devoted the next decade to characterizing the lamprey tauopathy model19-26 and examining the effects of anti-aggregation agents on tau-induced neurotoxicity and intracellular turnover27. During this time, work in my laboratory showed that extracellular tau deposits derived from tau-expressing ABCs can accumulate during the course of degeneration19, 23 and that tau clearance via secretion is associated with the neuroprotective effects of a low molecular weight anti-aggregation agent (NNI3)27. The significance of this last finding (i.e. that human tau can be secreted from non-degenerating, fully differentiated neurons in situ) has recently become our major recent research focus. My current research focuses on the integration of tau pathobiology at the cellular level with intercellular aspects of tauopathy pathogenesis. Since tau is universally known as an exclusively intracellular protein which is never secreted to the extracellular space, it has been assumed until very recently that tau protein cannot be secreted and thus can only reach the CSF once the neurons that synthesized it have died. We recently showed that tau protein is secreted by viable neurons in both cell culture and in situ (i.e. lamprey ABC) models of AD without the aid of anti-aggregation agents such as NNI328, and that tau secretion requires the N terminus28 and is significantly inhibited by the presence of the N terminal exon 2 sequence29, confirming that tau release is due to an active biological process. This work challenged the assumption that tau release must be passive and was initially difficult to publish. However, our findings together with congruent findings in other systems-(i.e. that tau can be taken up into adjacent neurons in culture30 and can be transferred between neurons in a mouse model31) have kindled interest in interneuronal tau movement in the AD/tauopathy research community, since it is now becoming clear that tau secretion may have important ramifications for the development of AD diagnostics and possibly for our overall understanding of the role of tau pathobiology in human disease. We are currently characterizing the tau secretion mechanism in more detail using both lamprey and cell culture models and have begun to extend this work to human brain and CSF samples from AD patients, using the absence of exon 2 secreted tau has a specific biomarker to ask whether tau secretion plays a role in the genesis of elevated CSF-tau in AD32-33.

Education

  • Ph D: Biology, (1985), Yale University - New Haven, CT
    Supporting Area: Neurobiology
    Dissertation/Thesis Title: Morphological Plasticity Of Lamprey Central Neurons Evoked By Axonal And Dendritic Injury
  • BS: Biology, (1979), McGill University - Montreal, PQ Canada

Publications

  • Wojnarowicz, M., Tagge, C., Fisher, A., Gaudreau, A., Minaeva, O., Moncaster, J., Casey, N., Zhang, X., Miry, O., Vose, L., others, . (2016) "CHRONIC TRAUMATIC ENCEPHALOPATHY IN ATHLETES IN THE SUBACUTE PERIOD AFTER CONCUSSIVE IMPACT AND A MOUSE MODEL OF IMPACT CONCUSSION," 33:13 pp. A31–A31
  • Goldstein, L.E., Tagge, C.A., Fisher, A.M., Minaeva, O., Gaudreau, A., Zhang, X., Upreti, C., Ericsson, M., Wojnarowicz, M.W., Casey, N.F., others, . (2016) "EARLY CHRONIC TRAUMATIC ENCEPHALOPATHY IN YOUNG ATHLETES AFTER CONCUSSIVE CLOSED-HEAD IMPACT INJURY AND MOUSE MODEL OF IMPACT CONCUSSION," Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 7:12 pp. P628–P629
  • Saman, S., Lee, N.C., Inoyo, I., Jin, J., Li, Z., Doyle, T., McKee, A.C., Hall, G.F. (2014) "Proteins recruited to exosomes by tau overexpression implicate novel cellular mechanisms linking tau secretion with Alzheimer’s disease," Journal of Alzheimer’s Disease 38:1 pp. S47-70 1p
  • Goldstein, L.G., Fisher, A., Tagge, C., Wojnarowicz, M.W., Zhang, X.L., Sullivan, J.S., Upreti, C., Goletiani, C., Maglakelidze, G., Casey, N., Moncaster, J., Minaeva, O., Cormier, K., Kubilus, C., Chargin, D., Sharon, A., Hall, G.F., Kracht, J., Ericsson, M., Geiling, J., Stern, R.A., Cantu, R.C., Tanzu, R.E., Kowalt, N.E., Velisak, L., Cleveland, R.O., Stanton, P.K., McKee, A.C. (2012) "Blast exposure induces chronic traumatic encephalopathy and persistent defects in axonal conduction, synaptic plasticity, and hippocampal memory," Science Transl. Med. 4: pp. 134ra60
  • Hasan, S.K., Hall, G.F. (2012) "Chapter on clinical advances in diagnosing taupathy,"
  • Hall, G.F. (2012) "Dr. Melvin Cohen, a retrospective,"
  • Saman, S., Kim, W., Visnick, Y., Miro, S., Saman, S., Jackson, B., McKee, A., Alvarez, V., Lee, N., Hall, G.F. (2012) "Exosome-associated tau is secreted in taupathy models and is selectively phosphorylated in CSF samples in Alzheimer's Disease," Journal of Biol. Chem. 287: pp. 3842-3849
  • Hall, G.F. (2012) "Frontiers in Neurodegeneration,"
  • Hall, G.F., Patuto, B.A. (2012) "Is tau now ready for admission to the Prion club?," Prion 6:3 pp. 223-233
  • Bhatia, N., Hall, G.F. (2012) "Novel aspects of tau pathobiology: their implications for research strategies and disease modeling in Alzheimer's Disease," Translational Neuroscience 2012
  • Le, M., Kim, W., Lee, S., McKee, A.C., Hall, G.F. (2012) "nterstitial and intraventricular migration of secreted human tau in a vertebrate tauopathy model," American Journal of Neurodegener Disease
  • Saman, S., Doyle, T., Hall, G.F. (2012) "Proteomic analysis of the expression of secretion-associated proteins in Alzheimers Disease,"
  • Hall, G.F., Saman, S. (2012) "Secretion or Death? What is the Significance of elevated CSF-tau in early AD?," Comm & Integ Biol 5:6 pp. 1-4
  • Hall, G.F., Hasan, S.K. (2012) "Tau secretion and the biogenesis of CSF-tau - implications for how we view AD," Curr. Alz. Res.
  • Augustin, C., Hall, G.F. (2012) "The morphometry of cytoskeletal degeneration and tau-induced dendritic degeneration,"
  • Daneshvar, D.H., Alvarez, V.E., Lee, H., Hall, G.F., Wojtowicz, S.M., Baugh, C.M., Riley, D.O., Kubilus, C.A., Cormier, K.A., Jacobs, M.A. (2012) "The spectrum of disease in chronic traumatic encephalopathy,"
  • Lee, S., Kim, W., Li, Z., Hall, G.F. (2011) "Accumulation of vesicle-associated human tau in distal dendrites drives degeneration and tau secretion in an in situ cellular tauopathy model," International Journal of Alzheimer's disease pp. 1-16
  • Saman, S., Hall, G.F. (2011) "Analysis of tau associated proteins in secreted exosomes: Clues to tau-mediated neurodegeneration?," Alzheimer's & Dementia: The Journal of the Alzheimer's Association 7:4 pp. 0-0
  • Lee, S., Hall, G.F., Shea, T.B. (2011) "Potentiation of Tau Aggregation by cdk5 and GSK3," Journal of Alzheimer's Disease 26:2 pp. 355-364
  • Hall, G.F. (2011) "The biology and pathobiology of tau protein," Springer pp. 285-313
  • Hall, G.F. (2011) "What is the common link between protein aggregation and interneuronal lesion propagation in neurodegenerative disease?," Neurodegenerative Diseases - Processes, Prevention, Protection and Monitoring. InTech pp. 1-17
  • Kim, W., Lee, S., Jung, C., Ahmed, A., Lee, G., Hall, G.F. (2010) "Interneuronal transfer of human tau between Lamprey central neurons in situ," Journal of Alzheimer's Disease 19:2 pp. 647-664
  • Kim, W., Lee, S., Hall, G.F. (2010) "Secretion of human tau fragments resembling CSF-tau in Alzheimer's disease is modulated by the presence of the exon 2 insert," FEBS Letters 584: pp. 3085-3088
  • Honson, N.S., Jensen, J.R., Abraha, A., Hall, G.F., Kuret, J. (2009) "Small-molecule mediated neuroprotection in an in situ model of tauopathy," Neurotoxicity Research 15: pp. 274-283
  • Lee, S., Jung, C., Lee, G., Hall, G.F. (2009) "Tauopathy Mutants P301L, G272V, R406W and V337M accelerate neurodegeneration in the Lamprey In Situ Cellular Tauopathy Model," Journal of Alzheimer's Disease 16:1 pp. 99-111
  • Hall, G.F., Lee, S., Ferreira, A., Lee, G. (2008) "Mitochondrial clumping is a central feature in the Tau neurodegeneration mechanism in an in situ tauopathy model," Alzheimer's and Dementia 4:4 pp. S1, T184
  • Lee, S., Chu, B., Yao, J., Shea, T., Hall, G.F. (2008) "The glutamate-rich region of the larger lamprey neurofilament sidearm is essential for proper neurofilament architecture," Brain Research 1231: pp. 1-5
  • Hall, G.F., Yao, J. (2005) "Modeling Tauopathy: A range of complementary approaches," Biochim. Biophys. Acta 1739: pp. 224-239
  • Hall, G.F. (2004) "An in situ cellular model of human tau aggregation and neurofibrillary degeneration," Neurobiology of Aging 25:S2 pp. S7
  • Hall, G.F., Lee, S., Yao, J. (2002) "Neurofibrillary degeneration can be arrested in an in vivo cellular model of human tauopathy by application of a compound which inhibits tau filament formation in vitro," Journal of Molecular Neuroscience 19: pp. 251-260
  • Hall, G.F., Lee, V.M., Lee, G., Yao, J. (2001) "Staging of neurofibrillary degeneration caused by human tau overexpression in a unique cellular model of human tauopathy," The American Journal of Pathology 158:1 pp. 235-246
  • Hall, G.F., Chu, B., Lee, G., Yao, J. (2000) "Human tau filaments induce microtubule and synapse loss in vertebrate central neurons," Journal of Cell Science 113: pp. 1373-1387
  • Hall, G.F., Yao, J. (2000) "Neuronal morphology, axonal integrity, and axonal regeneration in situ are regulated by cytoskeletal phosphorylation in identified lamprey central neurons," Microscopy Research and Technique 48: pp. 32-46
  • Hall, G.F., Chu, B., Lee, S., Liu, Y., Yao, J. (2000) "The single neurofilament subunit of the lamprey forms filaments and regulates axonal caliber and neuronal size in vivo," Cell Motility Cytoskeleton 46: pp. 166-182
  • Hall, G.F. (1999) "Neuronal Morphology: Development and maintenance of neuronal polarity," Elsevier 2 pp. 1409-1413
  • Hall, G.F. (1999) "PHF-Tau from Alzheimer brain is rapidly dephosphorylated and degraded when injected into neurons in situ," Journal of Alzheimer's Disease 1: pp. 379-386
  • Hall, G.F., , Selzer, M.E., Kosik, K.S. (1997) "Cytoskeletal correlates to cell polarity loss following axotomy of lamprey central neurons," Journal of Neurocytol. 26: pp. 733-753
  • Hall, G.F., Yao, J., Lee, G. (1997) "Human tau overexpressed in identified lamprey neurons in situ is hyperphosphorylated in dendrites, induces somatodendritic accumulations of 10nm filaments, and causes degeneration of heavily expressing cells," Proceedings of the National Academy of Sciences 94: pp. 4733-4738
  • Pijak, D.S., Hall, G.F., Tenicki, P., Selzer, M.E. (1996) "Neurofilament packing density, phosphorylationstate and axon caliber in the lamprey CNS," Journal of Comp. Neurol. 368: pp. 569-581
  • Hall, G.F., Lee, V.M. (1995) "Neurofilament sidearm proteolysis is a prominent early effect of axotomy in lamprey giant central neurons," Journal of Comp. Neurol. 353: pp. 38-49
  • McHale, M.K., Hall, G.F., Cohen, M.J. (1995) "Ultrastructural analysis of early changes following axotomy in giant spinal axons of the lamprey," Journal of Comp. Neurol. 353: pp. 25-37
  • Hall, G.F., Kosik, S.K. (1993) "Axotomy-induced neurofilament phosphorylation is inhibited in situ by microinjection of PKA and PKC inhibitors into identified lamprey neurons," Neuron 10: pp. 613-625
  • Hall, G.F. (1993) "Cellular responses of identified lamprey central neurons to axonal and dendritic injury," Ann. N. Y. Acad. Sci. 679: pp. 43-64
  • Hall, G.F., Lee, V.M., Kosik, K.S. (1991) "Microtubule destabilization and neurofilament phosphorylation precede dendritic sprouting after close axotomy of lamprey central neurons," PNAS 88: pp. 5016-5020
  • Hall, G.F., Poulos, A., Cohen, M.J. (1989) "Sprouts emerging from the dendrites of axotomized lamprey central neurons have axonlike ultrastructure," Journal of Neuroscience 9: pp. 588-599
  • Hall, G.F., Cohen, M.J. (1988) "Dendritic amputation redistributes sprouting evoked by axotomy of lamprey central neurons," Journal of Neuroscience 8:10 pp. 3598-3606
  • Hall, G.F., Cohen, M.J. (1988) "The pattern of dendritic sprouting and retraction induced by axotomy in lamprey central neurons," Journal of Neuroscience 8:10 pp. 3584-3597
  • Cohen, M.J., Hall, G.F. (1986) "The control of neuron shape during development and regeneration," Neurochem. Pathol. 5: pp. 331-343
  • Hall, G.F., Cohen, M.J. (1983) "Extensive dendritic sprouting induced by close axotomy of central neurons in the lamprey," Science 222: pp. 518-521

Presentations

  • , March 2013 - Rome, Italy
  • Interneuronal spreading of extracellular tau via ventricular and meningeal surfaces in the lamprey tauopathy model and in chronic traumatic encephalopathy - 2013 International ADPD meeting, 2012 - Florence, Italy
  • - The AD and PD Lecture Series, May 2012 - Center for Neurological Disease, Harvard Medical School
  • - Infectivity & Exosomes Key Opinion Leader Meeting, March 2012 - South San Francisco, CA
  • , December 2011 - Massachusetts Medical Devices Development Center, Lowell, MA
  • Tau misprocessing leads to non-classical tau secretion via vesicle release - implications for the spreading of tau lesions in AD - Int Conf. Alz Dis. meeting, 2011 - Paris, France
  • Tracing tau-amyloid beta intravesicular interactions with nanoparticles - Int Conf. Alz Dis. meeting, 2011 - Paris, France
  • Morphometric analysis of tau-induced dendritic degeneration in situ, 2011 - Washington DC
  • Tau Toxicity and Tau Secretion: Are they Connected in Alzheimer's Disease?, October 2011 - Wallingford, CT
  • Analysis of tau associated proteins in secreted exosomes - clues to tau-mediated neurodegeneration?, July 2011
  • Tau secretion from M1C human neuroblastoma cells occurs via the release of exosomes - Keystone Meeting on Neurodegenerative diseases, February 2011 - Taos, NM
  • Does tau pathobiology in AD involve tau secretion and interneuronal tau transfer?, January 2011 - Bedford, MA
  • A novel AD diagnostic based on new finding concerning tau secretion, December 2010 - Cambridge, MA
  • Pathological tau processing, secretion and interneuronal transfer in cell culture and in situ, July 2010 - Sydney, Australia
  • Does tau pathobiology in AD involve tau secretion and interneuronal tau transfer?, May 2010 - Boston, MA

Intellectual Property

  • Patent - Hall, G.F., Hasan, S."Individual functionalized graphene layers for biosensing," UML 2012-008
  • Patent - Hall, G.F., Hasan, S."Neuropeptides for manufacturing nanoparticles for drug delivery across blood brain barrier," UML 2012-007
  • Patent - Hall, G.F., Kim, W.K., Lee, S."The identification of secreted human tau protein fragments as a diagnostic in human neurodegenerative disease," UML 2010-010
  • Patent - Hall, G.F."A novel, inexpensive method for the early diagnosis of Alzheimer's disease," US Patent Office Application #61299198 United States

Contracts, Fellowships, Grants and Sponsored Research

  • VA Merit Award (2012), -
    Hall, G.F.
  • Pilot Grant (2012), Grant - Massachusetts Bay Community College
    Hall, G.F.
  • Pilot Grant (2010), Grant - Boston University Alzheimer's Disease Center
    Hall, G.F. (Principal)
  • Research Contract (2009), Contract - Neuronautics Inc.
    Hall, G.F. (Other)
  • STTR-1 Grant (2005), Grant - National Institutes of Health (with Neuronautics Inc.)
    Hall, G.F. (Other)
  • Research Grant (2001), Grant - National Institutes of Health
    Hall, G.F. (Principal)
  • IIRG (2000), Grant - Alzheimer's Association
    Hall, G.F. (Principal)
  • Research Grant (1996), Grant - National Institutes of Health
    Hall, G.F. (Principal)
  • "First" Award (1992), - National Institutes of Health
    Hall, G.F. (Principal)
  • SCRF Grant (1994), Grant - Paralyzed Veterans of America
    Hall, G.F.
  • Pilot Award (1994), - American Federation for Aging Research
    Hall, G.F.