Increasing attention has been drawn to the microtubules in the aging brain; and to their role in the genesis of neurofibrillary tangles, a feature of both Alzheimer's disease and to a lesser extent of normal aging. Neuronal microtubules have likely undergone modifications which skew the microtubule dynamic toward a polymerized state necessary for the maintenance of transport over relatively long distances. Brain microtubule-associated proteins (MAPs) are thought to have a role in the stabilization of microtubules and, because some MAPs are so highly compartmentalized within neurons, they may also have a role in the correct sorting of molecules to appropriate axonal or dendritic destinations. MAP2 is an approximately 280 kDa phosphoprotein which is abundant in brain and enriched in the somatodendritic compartment of neurons. In several experimentally induced conditions which result in filamentous aggregates MAP2 becomes dissociated from the microtubule and collects within the aggregate. Similarly MAP- immunoreactivity is found within the region of the neurofibrillary tangle, an area devoid of microtubules. A description of the molecular structure of the MAP2 microtubule-binding domain and the modifications which the molecule undergoes when unassociated with the microtubule may be relevant to the pathogenesis of neurofibrillary tangles. MAP2 was previously shown to share epitopes with the Alzheimer neurofibrillary tangle, but not to be an integral part of the paired helical filament. An important integral component of the paired helical filament is now thought to be another MAP designated tau protein, which is found in a distribution complementary to MAP2, in the axonal portion of neurons. Recent data suggests that tau protein in the neurofibrillary tangle may be ubiquitinated. We propose to study both the potential for ubiquitination of MAP2 and tau in vitro and to what extent these conjugates might serve as substrates for ubiquitin-mediated proteolysis. One of the features of the Alzheimer lesions is their violation of the highly compartmentalized neuronal topography: the axonal protein, tau, aggregates in the MAP2-rich somatodendritic compartment of the pyramidal cell. MAP2 and tau cDNA probes will be used to demonstrate ribosomal topography and their possible contribution of the compartmentalization. Finally, we propose to initiate dynamic studies of possible roles for the MAPs in neuronal transport.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG006172-04
Application #
3117048
Study Section
Neurology C Study Section (NEUC)
Project Start
1985-05-01
Project End
1990-12-31
Budget Start
1988-01-01
Budget End
1988-12-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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Oblinger, M M; Argasinski, A; Wong, J et al. (1991) Tau gene expression in rat sensory neurons during development and regeneration. J Neurosci 11:2453-9
Kosik, K S; Caceres, A (1991) Tau protein and the establishment of an axonal morphology. J Cell Sci Suppl 15:69-74
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. Proc Natl Acad Sci U S A 88:5016-20
Baas, P W; Pienkowski, T P; Kosik, K S (1991) Processes induced by tau expression in Sf9 cells have an axon-like microtubule organization. J Cell Biol 115:1333-44
Kosik, K S; Orecchio, L D; Schnapp, B et al. (1990) The primary structure and analysis of the squid kinesin heavy chain. J Biol Chem 265:3278-83
Kosik, K S; Crandall, J E; Mufson, E J et al. (1989) Tau in situ hybridization in normal and Alzheimer brain: localization in the somatodendritic compartment. Ann Neurol 26:352-61
Kosik, K S; Orecchio, L D; Bakalis, S et al. (1989) Developmentally regulated expression of specific tau sequences. Neuron 2:1389-97
Kosik, K S; Orecchio, L D; Binder, L et al. (1988) Epitopes that span the tau molecule are shared with paired helical filaments. Neuron 1:817-25

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