The actin cytoskeleton makes primary contributions to the maintenance of cell shape, and the production of force for cell movements in eucaryotic cells. Alterations in the structure and function of the cytoskeleton are implicated in numerous diseases and conditions including aging, and neurodegenerative disease. Hirano bodies are actin rich inclusions associated with normal aging, and with Alzheimer's disease, but the dynamics and physiological function of Hirano bodies are poorly understood. Our laboratory has developed models for the study of the Hirano bodies in the social amoeba Dictyostelium, cultured mammalian cells, and a transgenic mouse Hirano body model. These models have enabled our studies of the cell biological mechanisms for the formation and the degradation of Hirano bodies, and for studies of the role of these inclusions in the progression of disease. Two current research areas are highlighted below:
Hirano bodies and Alzheimer's Disease Pathology
Alzheimer’s disease is a progressive neurodegenerative condition characterized by loss of synapses, loss of neurons, progressive cognitive decline, and loss of synaptic plasticity. These aspects of Alzheimer’s pathology can be investigated using transgenic mouse models of this disease. Crosses of our Hirano body mouse with Alzheimer’s disease model mice will allow study of the impact of Hirano bodies on the development of pathology, and loss of memory in these mouse models. Findings that Hirano bodies either significantly accelerate or impair the development of pathology would identify Hirano bodies are a novel pathway for development of therapeutics for the treatment of Alzheimer’s disease.
Association of AICD and Tau with Hirano bodies
The amyloid precursor protein and tau are the two proteins most firmly implicated in the pathology of Alzheimer’s disease. Both proteins have been localized to Hirano bodies in Alzheimer’s brain, and we have confirmed the localization of both proteins with our model Hirano bodies. We are investigating the isoforms of tau and the specific regions of APP that associate with Hirano bodies, the mechanism of these associations, and the physiological function. Results of an initial study show that Hirano bodies sequester the intracellular domain of APP (AICD), and modulate AICD dependent cell death and AICD dependent gene transcription. Studies of the effects of Hirano bodies on toxicity induced by other regions of APP and by tau are in progress.
Molecular cell biology of the Actin Cytoskeleton; Alzheimer's Disease; Aging; Hirano bodies
Ha, S., Furukawa, R., Stramiello, M., Wagner, J.J., and Fechheimer, M. (2011). Transgenic Mouse Model for the Formation of Hirano Bodies. BMC Neurosci. 12:97. [Epub ahead of print]
Ha, S., Furukawa, R., and Fechheimer, M. (2011). Association of AICD and Fe65 with Hirano bodies reduces transcriptional activation and initiation of apoptosis. Neurobiol Aging. 32:2287-98.
Kim, D.-H., R. Furukawa, and M. Fechheimer. 2009. Degradation of Hirano Bodies by Autophagy 5, 44-51.
Davis, R. C., Furukawa, R., and M. Fechheimer, 2008. A Mammalian Cell Culture Model for the Formation of Hirano Bodies, Acta Neuropathologica 115, 205-217.
Stich, R. W., G. A. Olah, K. A. Brayton, W. C. Brown, M. Fechheimer, K. Green-Church, S. Jittapalapong, K. M. Kocan, T. C. McGuire, F. R. Rurangirwa, and G. H. Palmer. 2004. Identification of a novel Anaplasma marginale appendage-associated protein that localizes with actin filaments during intraerythrocytic infection. Infection and Immunity 72, 7257-7264.
Maselli, A., R. Furukawa, S. A. M. Thomson, R. C. Davis, and M. Fechheimer. 2003. Formation of Hirano Bodies Induced by Expression of an Actin Cross-linking Protein With a Gain of Function Mutation. Eucaryotic Cell 2, 778-787.
Maselli, A. G., R. Davis, R. Furukawa, and M. Fechheimer. 2002. Formation of Hirano Bodies in Dictyostelium and Mammalian Cells Induced by Expression of a Modified form of an Actin Cross-linking Protein. J. Cell Science 115, 1939-1952.
Lim, R. W. L., R. Furukawa, and M. Fechheimer. 1999. Evidence of Intramolecular Regulation of the Dictyostelium discoideum 34,000 dalton F-actin Bundling Protein. Biochemistry 38, 16323-16332.
Lim, R. W. L., R. Furukawa, S. Eagle, R. C. Cartwright, and M. Fechheimer. 1999. Three Distinct F-actin Binding Sites in the Dictyostelium discoideum calcium-regulated 34,000 dalton Actin Bundling Proten. Biochemistry 38, 800-812.
Rivero, F., R. Furukawa, M. Fechheimer, and A. A. Noegel. 1999. Three actin cross-linking proteins, the 34 kDa actin-bundling protein, a-actinin, and ABP-120, have both unique and redundant roles in the growth and development of Dictyostelium. J. Cell Science 112, 2737-2751.
Clem, R. J., M. Fechheimer, and L. K. Miller. 1991. A Baculovirus Gene Required to Prevent Apoptosis During Infection of Insect Cells. Science 254, 1388-1390.
Fechheimer, M., and J. J. Cebra. 1982. Phosphorylation of Lymphocyte Myosin Catalyzed In Vitro and In Intact Cells. J. Cell Biol. 93, 261-268.