Garth Hall, Biological Sciences, Biomedical Engineering
Garth Hall, Biological Sciences, Biomedical Engineering
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 Alzheimer’s 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 Alzheimer’s 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.
- Hall, G. F. and M. J. Cohen (1983) Extensive dendritic sprouting induced by close axotomy of central neurons in the lamprey. Science 222: 518-521.
- Cohen, M. J. and G. F. Hall (1986) The control of neuron shape during development and regeneration. Neurochem. Pathol. 5: 331-343.
- Hall, G. F. and M. J. Cohen (1988a) The pattern of dendritic sprouting and retraction induced by axotomy of lamprey central neurons. J. Neurosci. 8(10): 3584-3597.
- Hall, G. F. and M. J. Cohen (1988b) Dendritic amputation redistributes sprouting evoked by axotomy in lamprey central neurons. J. Neurosci. 8(10): 3598-3606.
- Hall, G. F., A. Poulos and M. J. Cohen (1989) Sprouts emerging from the dendrites of axotomized lamprey central neurons have axonlike ultrastructure. J. Neurosci. 9: 588-599.
- Kowall N. W., Kosik K. S. (1987) Axonal disruption and aberrant localization of tau protein characterize the neuropil pathology of Alzheimer’s disease. Ann Neurol. 22: 639-643.
- Braak H., Braak E. (1988) Neuropil threads occur in dendrites of tangle- bearing nerve cells. Neuropathol Appl Neurobiol. 14:39-44.
- Ihara, Y. (1988) Massive somatodendritic sprouting of cortical neurons in Alzheimer's Disease. Brain Res 459: 138-144.
- Hall G. F. (1999) Neuronal Morphology: Development and maintenance of neuronal polarity. Encyclopedia of Neuroscience, ed Adelman & Smith 2 ed New York, Elsevier. pp 1409-1413.
- Hall, G. F., V. M-Y Lee and K. S. Kosik (1991) Microtubule destabilization and neurofilament phosphorylation precede dendritic sprouting after close axotomy of lamprey central neurons PNAS 88: 5016-5020.
- Hall, G. F. (1993) Cellular responses of identified lamprey central neurons to axonal and dendritic injury. Ann. N. Y. Acad. Sci. 679: 43-64.
- Hall, G. F. and K. S. Kosik (1993) Axotomy-induced neurofilament phosphorylation is inhibited in situ by microinjection of PKA and PKC inhibitors into identified lamprey neurons. Neuron 10: 613-625.
- Hall, G. F., J. Yao, M. E. Selzer and K. S. Kosik (1997) Cytoskeletal correlates to cell polarity loss following axotomy of lamprey central neurons J. Neurocytol. 26: 733-753.
- McHale, M. K., G. F. Hall and M. J. Cohen (1995) Ultrastructural analysis of early changes following axotomy in giant spinal axons of the lamprey. J. Comp. Neurol. 353: 25-37.
- Hall, G. F. and V. M-Y. Lee (1995) Neurofilament sidearm proteolysis is a prominent early effect of axotomy in lamprey giant central neurons. J. Comp. Neurol. 353: 38-49.
- Pijak, D. S., G. F. Hall, P. Tenicki and M. E. Selzer (1996) Neurofilament packing density, phosphorylationstate and axon caliber in the lamprey CNS. J. Comp. Neurol. 368: 569-581.
- Hall, G. F., Chu, B., Lee, S., Liu, Y. and J. Yao. (2000) The Single Neurofilament Subunit of the Lamprey Forms Filaments and Regulates Axonal Caliber and Neuronal Size In Vivo. Cell Motil. Cytoskel. 46: 166-182.
- Lee, S., Chu, B., Yao, J., Shea, T. and Hall, G.F. (2008) The glutamate-rich region of the larger lamprey neurofilament sidearm is essential for proper neurofilament architecture. Brain Res. 1231, 1-5.
- Hall, G. F., J. Yao and G. Lee. (1997) Human tau overexpressed in identified lamprey neurons in situ is hyperphosphorylated in dendrites, induces somatodendritic accumulations of 10 nm filaments, and causes degeneration of heavily expressing cells PNAS 94: 4733-4738.
- Hall, G. F. (1999) PHF-Tau from Alzheimer Brain is Rapidly Dephosphorylated and Degraded When Injected Into Neurons in situ. J. Alz. Dis. 1:379-386.
- Hall, G. F., and J. Yao (2000) Neuronal Morphology, Axonal Integrity and Axonal Regeneration In Situ are Regulated by Cytoskeletal Phosphorylation in Identified Lamprey Central Neurons. Microscopy Res.Tech. 48: 32-46.
- Hall, G. F., Chu, B., Lee, G. and J. Yao. (2000) Human Tau Filaments Induce Microtubule and Synapse Loss in Vertebrate Central Neurons J. Cell Science. 113:1373-1387.
- Hall, G. F., Chu, B., Lee, V. M-Y., and J. Yao (2001) Hyperphosphorylation of human tau is correlated with progressive stages of cytodegeneration in an in vivo model of neurofibrillary degenerative disease. Am. J. Path 158: 235-246.
- Hall, G. F. and Yao, J. (2005) Modeling Tauopathy. A range of complementary approaches. In Biochim. Biophys. Acta 1739: 224-239.
- Honson, N.S., Jensen, J.R. Abraha, A., Hall, G.F., and Kuret, J. (2009) Small-molecule mediated neuroprotection in an in situ model of tauopathy. Neurotoxicity Res., 13,15(3):274-83.
- Lee, S., Jung, C., Lee, G and Hall, G. F. (2009) Tauopathy Mutants P301L, G272V, R406W and V337M accelerate neurodegeneration in the Lamprey In Situ Cellular Tauopathy Model. J. Alz Dis. 16(1):99-111.
- Hall, G. F., Lee, S., and J. Yao (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. J. Mol. Neurosci 19: 253-260.
- Kim, W., Lee, S., Jung, C., Ahmed, A., Lee, G. and Hall, G.F. (2010a). Interneuronal Transfer of Human Tau Between Lamprey Central Neurons in situ. J. Alz Dis. 19(2)2: 647–664.
- Kim, W., Lee, S. and Hall, G.F. (2010b) Secretion of human tau fragments resembling CSF-tau is modulated by the presence of the exon 2 insert. FEBS Letters 584: 3085–3088.
- Frost B., Jacks R. L. and Diamond, M.I. (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284: 12845-12852.
- Clavaguera F., Bolmont T., Crowther R.A., Abramowski D., Frank S., Probst A., Fraser G., Stalder A.K., Beibel M., Staufenbiel M., Jucker M., Goedert M., and Tolnay M. (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11: 909-913.
- Hall, G.F. (2011) 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 Paris, France.
- Saman, S. and Hall, G. F. (2011) Tau secretion from M1C human neuroblastoma cells occurs via the release of exosomes. Keystone Meeting on Neurodegenerative diseases, Feb 2011, Taos NM.
B.Sc., Biology, McGill University, 1979
Ph.D., Biology, Yale University, 1985