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Structural Neurobiology Laboratory

Faculty Director: Michelle A. Poirier, Ph.D.

Link to PubMed publications for Poirier, Michelle A

The laboratory of structural neurobiology is focused on the role of protein aggregation in neurodegenerative diseases and how abnormal protein structure may lead to cell toxicity. We have a particular interest in the huntingtin protein, known to be responsible for Huntington’s disease, as well as alpha-synuclein, one of the proteins implicated in Parkinson’s disease. We are using biochemical and biophysical techniques in our studies in vitro, and both cell culture and transgenic mouse models to study these diseases in vivo. With this combination of in vitro and in vivo studies, we hope to gain a better understanding of the pathogenesis of these disorders, and to work towards the development of novel therapeutic compounds.

The laboratory welcomes undergraduates, graduate students, and postdoctoral fellows to study these diseases.  Those interested can contact Dr. Poirier directly.


Yair Porat, Ph.D., postdoctoral fellow
Zhipeng Hou, B.S., research assistant
Guarav Srivastava, undergraduate student


Huntington’s disease (HD) arises from an expanded polyglutamine region in the N-terminus of the HD gene product, huntingtin.  Aggregation of the huntingtin protein is a complex, multistep process of protein conformational change and results in the formation of inclusions in HD patient brain tissue. These inclusions contain N-terminal fragments of the huntingtin protein and are comprised of fibrillar material resembling amyloid. However, the role of huntingtin inclusions in toxicity has been controversial. More recent evidence suggests that inclusions may represent an end-stage manifestation of the aggregation process and that species formed early in aggregation are responsible for toxicity. While the inclusions may not be the major toxic species in HD, the aggregation process appears to be linked to pathogenesis.

The Structural Neurobiology laboratory is currently pursuing two areas of study. First using in-vitro biochemical techniques and morphological analyses, we have recently observed oligomeric and protofibrillar structures formed early in the huntingtin aggregation process. Similar such species have been observed for other amyloidogenic proteins, including A-beta of Alzheimer’s disease and alpha-synuclein of Parkinson’s disease and have a putative role in cyotoxicty. We are developing a live cell imaging assay to follow huntingtin aggregation in cultured cells in the hopes of identifying  early aggregation species that could potentially serve as targets for therapeutic intervention.

Structural Lab Graphic

Figure Legend: Htt exon-1-transfected cells were analyzed for toxicity by the TUNEL assay. Expression of htt proteins was detected by immunostaining (left panels) and shows aggregates for htt exon-1 beta turn former (top first panel) transfected cells and diffuse cytoplasmic staining for cells containing htt exon-1 beta strand breaker (bottom first panel). TUNEL positive cells are shown in red and are observed for the two aggregate-containing cells (top second panel). The merged image (top third panel) demonstrated that the two TUNEL positive nuclei are co-localized with polyQ aggregates. Phase contrast image of the same cells (top fourth panel) shows that these two cells are rounded and on top of healthy cells. The two cells expressing htt exon-1 beta strand breaker were not TUNEL positive (bottom second panel). A phase contrast image (bottom fourth panel demonstrates that both of these cells were healthy.

In a second area of investigation, we are studying the relationship between abnormal huntingtin polyglutamine structure and toxicity.  Recently, we developed a structure-based method to test an alternating beta-strand/beta-turn (compact beta-sheet structure) model of mutant huntingtin aggregation and toxicity in mammalian cell culture.  Based on our findings, a huntingtin protein designed to form a compact-beta sheet structure was able to aggregate in cultured mammalian cells and in primary cortical neurons isolated from embryonic mice.  Toxicity experiments determined that this protein was also toxic in both cell culture systems. We are currently developing an HD compact beta-transgenic mouse model to determine the validity of this structure in vivo. 

Taken together, these studies will help delineate early stages of huntingtin polyglutamine aggregation, and will provide insight into the relationship between mutant polyglutamine structure and neurotoxicity in HD. A better understanding of the pathogenic pathways of HD could lead to rational therapies that may have implications for other neurodegenerative diseases of protein aggregation.


Poirier, M.A. , Jiang, H., and Ross, C.A.  A structure-based analysis of huntingin mutant polyglutamine aggregation and toxicity: evidence for a compact beta-sheet structure.  Human Molecular Genetics (2005) 14: 765-774.

Poirier, M.A., Li, H., Macosko, J., Cai, S., Amzel, M.and Ross, C.A.  Huntingtin spheroids and protofibrils as precursors in polyglutamine fibrillization. The Journal of Biological Chemistry  (2002) 277: 41032-41037.

Jiang, H., Poirier, M.A., Liang, Y., Zhong, Pei, Weiskittel, C.E., Smith, W.W., DeFranco, D.B., and Ross, C.A.  Depletion of CBP is directly linked with cellular toxicity caused by mutant huntingtin.  Neurobiology of Disease (2006) 23: 543-51.

Schilling, G., Klevytska, A., Tebbenkamp, A.T.N., Juenemann, K., Cooper, J., Gonzalez, V., Slunt, H., Poirier, M. A, Ross, C.A., and Borchelt, D.R.  Characterization of huntingtin pathologic fragments in human Huntington disease, transgenic mice, and cell models.  Journal of Neuropathology and Experimental Neurology  (2007) 66: 313-320.

Schilling, G., Savonenko, A.V., Klevytska, A., Morton, J.L., Tucker, S.M., Poirier, M.A., Gale, A., Chan, N., Gonzales, V., Slunt, H.H., Coonfield, M.L., Jenkins, N.A., Copeland, N.G., Ross, C.A., and Borchelt, D.R.  Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice. Human Molecular Genetics (2004) 13: 1599-1610.

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