|
|
|
|
|
| First Name: | Garth | | Last Name: | Hall | | Title: | Associate Professor | | Advanced Degrees: | Ph.D. | | Affiliation: | University of Massachusetts Lowell | | Department: | Biological Sciences | | Street Address 1: | 519 Olsen Hall | | Street Address 2: | 198 Riverside Street | | City: | Lowell | | State/Province: | MA | | Zip/Postal Code: | 01854 | Country/Territory: | U.S.A. | | Phone: | 978 934 2893 | | Fax: | 978 934 3044 | | Email Address: |  |
Disclosure:
(view policy)
|
Member reports no financial or other potential conflicts of interest. [Last Modified: 30 January 2010]
|
|
|
View all comments by Garth Hall
|
Alzheimer Disease, Prion Diseases, Stroke and Trauma, Parkinson Disease, Tauopathies
|
Animal Models, Microscopy, Molecular and Cell biology, Tau/Cytoskeleton, Neurobiology, Diagnosis
|
Long term interest in cytoskeleton, neuronal polarity and its role in AD/tauopathy. Also am interested in tau-NF interactions and synergistic interactions between tau, PrP and alpha synuclein, and their possible involvement in endocytosis/secretion of tau in AD.
Have studied the cytopathology of tau in an situ cellular model (lamprey) since 1995, published a study of tau-driven neurodegeneration in 1997. This was the first study to demonstrate tau-induced cytotoxicity in any system, and highlighted the need for in situ modeling approaches to tauopathy.
Just now publishing a study demonstrating 2 mechanisms of tau secretion from neurons using both the lamprey in situ model and human neuroblastoma-based cell culture models. We showed that tau is actively secreted via a) a degeneration-independent mechanism replicable in cell culture which produces N terminal species similar to those seen in human CSF and b) an aggregation/degeneration associated mechanism (see my hypothesis below) that can result in transsynaptic tau transfer when mutant tau is involved.
These findings have are similar to the demonstrations of tau transfer (Clavaguera et. al 09) and uptake (Frost et. al. 09) published recently in other models, and contain additional details that have important ramifications for the development of AD diagnostics and possibly for our overall understanding of the role of tau pathobiology in human disease.
|
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 Proceedings of the National Academy of Sciences 88: 5016-5020.
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 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 Proceedings of the National Academy of Sciences 94: 4733-4738.
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. American Journal of Pathology 158: 235-246.
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
Lee, S., Chu, B., Yao, J., Shea, T. B., 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.
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.
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. J. Alz Dis. 19. in press.
|
Our relatively poor understanding of the basic biology of the key actors in these diseases (tau, APP, PrP come to mind especially).
This is compounded by the tendency of tacit "conventional wisdom" assumptions to dominate what should be a more open minded debate about key hypotheses which drive the creation and use of expensive and widely used mouse models. |
Lee HJ, Patel S, Lee SJ (2005) Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J
Neurosci 25, 6016-6024.
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel
M, Jucker M, Goedert M, Tolnay M (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell
Biol 11, 909-913.
Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284, 12845-12852. |
I would make some mice which could ask basic processing questions about key players in the NDD field, rather than attempt to perfectly mimic human diseases, since I think our understanding of the underlying biology is much less advanced than we tend to think it is. I'd start with some tau deletion-expressing knock-in tg mice (my current focus is on the mechanisms of tau protein secretion and roles they might play in neurodegenerative disease), but there are many other good candidate proteins for such modeling.
I am quite bemused by the fact that the only straightforward tau deletion mouse around (AFAIK, at least) is Lars Ittner's/Jurgen Gotz' delta tau mouse, which is proving quite interesting. There should be many more tg mice of this type made and studied before we can extrapolate knowledge about tau biology and pathobiology obtained in cell culture models to whole animal models with sufficient skill to produce generally useful disease models for testing therapeutics. This applies to plenty of other key proteins in NDDs aside from tau, as well. |
That tau, PrP ASN and APP/Abeta are all processed similarly in neurons and interact with one another when toxic - they are phosphorylated in lipid rafts by fyn and related TKs, and are part of the TK downstream signal transduction pathway, which involves oligomerization, raft patching and endocytosis, followed by MT-mediated trafficking and eventually exocytosis from elsewhere in the neuron where degeneration and exocytosis are being driven by high Ca++. In disease circumstances, this can result in the synergistic interneuronal movement of these proteins and their active secretion to the CSF.
Obviously, this is a larger framework than a single hypothesis, but it is consistent with existing literature and we will soon be publishing a study showing significant circumstantial support for much of this in the lamprey model. |
We are approaching this problem by building a culture model of tau secretion, uptake and transneuronal transfer. We are currently working to determine if phosphorylation of tau at Y18 is involved in tau endocytosis and /or membrane shedding in cell culture and if these events are potentiated by the introduction of ASN.
|
I'd be satisfied with tau-ASN and/or tau-PrP following this path!
Tau secretion is clearly "unconventional", and may involve direct membrane shedding as well as/instead of fyn-driven endocytosis, especially in the CSF tau, or "diffuse" secretion pathway (see Kim et al in the ARF current papers list). I doubt if all of the details of the above hypothesis will pan out, but the major part of it already seems likely. The key question is to what degree these events actually contribute to human disease, especially since they differ significantly from the hypotheses currently driving most therapeutics development. |
|
|
|
|
|
|
Home
