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FORMATION, STABILITY, AND STRUCTURE OF HIRANO BODIES USING A LIVE CELL SYSTEM

Dr. Andres G. Maselli

Andrew G. Maselli, Ph.D.

Department of Biological Sciences

As the human population ages, neurodegenerative diseases have become a major health concern. Substantial progress has been made, but the underlying causes of these diseases are complex and poorly understood. One of the least understood structural manifestations of neurodegenerative disorders are Hirano bodies. Hirano bodies are actin-based inclusions, which have been identified in the brains of individuals with a broad range of neurodegenerative disorders including Alzheimer’s disease. The contribution of Hirano bodies to neurodegeneration is a mystery. It is unclear if Hirano bodies are the causative agents of the pathology observed or a morphological marker for other changes occurring as part of the degenerative process.

To understand the process that triggers the formation of Hirano bodies it is necessary to have a model system in which the molecular mechanisms for the formation of Hirano bodies can be characterized in living cells. We have shown that the expression of a truncated 34 kDa actin binding protein with uncontrolled actin cross-linking activity can induce the formation of Hirano bodies in the eukaryotic model system Dictyostelium discoideum (Maselli et al., 2003; Maselli et al., 2002). The model Hirano bodies formed in Dictyostelium have ultrastructural and biochemical characteristics that are similar to that of human Hirano bodies (Maselli et al., 2002). Our hypothesis is that when small amounts of an uncontrolled actin crosslinker are present in the cell, a cascade of events begins which leads to Hirano body formation. Preliminary data suggests that a fragment of the actin binding protein fimbrin initiates actin inclusion formation. This is an exciting development because Dictyostelium fimbrin is a clear homology to human plastin. The ultimate goal is to understand the connection between actin binding protein fragments and human Hirano bodies. One of the logical sources for these actin binding protein fragments in brain cells is from the cell's own proteins that have been cleaved by proteases. We propose to investigate the cascade of events leading the Hirano body formation and identify candidate truncated actin binding proteins using Dictyostelium as a model system

This project provides a number of excellent opportunities for student undergraduate and graduate. Our laboratory uses a broad range of molecular biology, cell biology and microscopy techniques. The generous support of the MBRS program has provided state of the art research equipment, which, is available for student driven research. Helping students develop as independent scientists and make significant contributions to this research project is a core mission of the laboratory.

RECENT PUBLICATIONS & PRESENTATIONS

PUBLICATIONS

Maselli, A., Thomson, S. A. M., Davis, R., Furukawa, R., and Fechheimer, M. (2003) “Formation of Hirano Bodies Induced by Expression of a Modified Form of an Actin Cross-linking Protein with Point Mutations that Activate Actin Binding.” Eukaryotic Cell 4:778-787.

Furukawa, R., Maselli, A., Thomson S. A. M., Lim. R.W., and Fechheimer M. (2003) “Calcium Regulation of Actin Cross-linking Is Important for Function of the Actin Cytoskeleton in Dictyostelium.” Journal of Cell Science 116: 187-196.

Fechheimer, M., Furukawa, R., Maselli A., and Davis R. (2002) “Hirano Bodies in Health and Disease” Trends in Molecular Medicine 8: 590-591.

Maselli, A.G., Davis, R., Furukawa, R., Fechheimer M. (2002). “Formation of Hirano Bodies in Dictyostelium and Mammalian Cells Induced by Expression of a Modified form of an Actin-crosslinking Protein.” Journal of Cell Science 115:1939-49.

Maselli, A., Laevsky, G., Knecht, D. (2002). “Kinetics of Binding, Uptake and Degradation of Live Fluorescent (DsRed) Bacteria by Dictyostelium discoideum.” Microbiology 148:413-20.

PRESENTATIONS
(RISE students are indicated in boldface.)

J. Ramos*, M. Myrthil, K. Stone, and A. Maselli. Comparison Of Hirano Body Formation Initiated By An F-Actin Stabilizing Drug And A Truncated Actin Bundling Protein, Illinois State Academy of Science 99th annual meeting. Springfield, IL. (Presented by J. Ramos)

J. Ramos, A. Maselli (2006). Exploring Drug Stabilized F-actin as a Live Cell Model for Hirano Body Formation. The American Society of Cell Biology 46th annual meeting. (Presendted by J. Ramos)

Ran-Der Hawag, Chin-Chi Chen, Raymond Washington, Andrew G. Maselli and David A. Knceht (2006). Regulation of Actin Cytoskeletal Architecture by Fimbrin A. International Dictyostelium Conference, Santa Fe, NM. (Presented by Ran-Der Hwang)

Vashati Butler, Marsha Myrthil, and Andrew Maselli, Hirano Bodies Are Found In The Cytoplasmic Bridge Between Dividing Dictystelium Cells, 9th Annual Illinois LS-AMP Student Research Conference, Glenview, Illinois, October 6-7, 2006.

J. F. Reyes, A. G. Maselli (2005) The Formation of GFP-Tagged Hirano Bodies in Dictyostelium discoideum after Inducible Expression of a Truncated Actin Bundling Protein , American Society of Cell Biology 45th annual meeting.

J. F. Reyes and A. G. Maselli (2005). Studying the formation of Hirano Bodies in Dictyostelium discoideum in vivo using vectors with inducible promoters, Illinois State Academy of Science 97th Annual meeting. Galesburg, IL.

R. Furukawa, L. F. Hoagland, R. C. Davis, A. G. Maselli, M. Fechheimer (2004) ; Myosin II Is Required for Hirano Body Formation. 44st American Society for Cell Biology Annual Meeting, Washington, D.C.

Dr. Andrew Maselli (far left) and his research team.

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Page Updated 09/18/07

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