Identifying Polyglutamine Protein Species in situ that Best Predict Neurodegeneration

Authors

Jason Miller, University of California, San Francisco
Montserrat Arrasate, University of California, San Francisco
Elizabeth Brooks, University of California, San Francisco
Clare Peter Libeu, University of California, San Francisco
Justin Legleiter, University of California - San Francisco
Danny Hatters, University of California, San Francisco
Jessica Curtis, University of California, San Francisco
Kenneth Cheung, University of California, San Francisco
Preethi Krishnan, University of California, San Francisco
Siddhartha Mitra, University of California, San Francisco
Kartika Widjaja, University of California, San Francisco
Benjamin A. Shaby, Cornell University
Gregor P. Lotz, University of California - San Francisco
Yvonne Newhouse, Gladstone Institute of Neurological Disease
Emily M. Sontag, Marquette UniversityFollow
Alex Osmand, University of Tennessee
Michelle Gray, University of California, Los Angeles
Vanitha Thulasiramin, Bio-Rad Laboratories
Frederic Saudou, Institute Curie, France
Mark Segal, University of California, San Francisco
X William Yang, University of California, Los Angeles
Eliezer Masliah, University of California, San Francisco
Leslie M. Thompson, University of California, Irvine
Paul J. Muchowski, University of California - San Francisco
Karl H. Weisgraber, University of California, San Francisco
Steven Finkbeiner, University of California, San Francisco

Document Type

Article

Publication Date

12-2011

Publisher

Nature Publishing Group (Macmillan Publishers Limited)

Source Publication

Nature Chemical Biology

Source ISSN

1552-4450

Original Item ID

DOI: 10.1038/nchembio.694

Abstract

Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal coping response to more toxic forms of polyQ. The exact structure of these more toxic forms is unknown. Here we show that the monoclonal antibody 3B5H10 recognizes a species of polyQ protein in situ that strongly predicts neuronal death. The epitope selectively appears among some of the many low-molecular-weight conformational states assumed by expanded polyQ and disappears in higher-molecular-weight aggregated forms, such as inclusion bodies. These results suggest that protein monomers and possibly small oligomers containing expanded polyQ stretches can adopt a conformation that is recognized by 3B5H10 and is toxic or closely related to a toxic species.

Comments

Accepted version. Nature Chemical Biology, Vol. 7, No. 12 (December 2011): 925-934. DOI. © 2011 Nature Publishing Group (Macmillan Publishers Limited). Used with permission.

Recommended Citation

Miller, Jason; Arrasate, Montserrat; Brooks, Elizabeth; Peter Libeu, Clare; Legleiter, Justin; Hatters, Danny; Curtis, Jessica; Cheung, Kenneth; Krishnan, Preethi; Mitra, Siddhartha; Widjaja, Kartika; Shaby, Benjamin A.; Lotz, Gregor P.; Newhouse, Yvonne; Sontag, Emily M.; Osmand, Alex; Gray, Michelle; Thulasiramin, Vanitha; Saudou, Frederic; Segal, Mark; Yang, X William; Masliah, Eliezer; Thompson, Leslie M.; Muchowski, Paul J.; Weisgraber, Karl H.; and Finkbeiner, Steven, "Identifying Polyglutamine Protein Species in situ that Best Predict Neurodegeneration" (2011). Biological Sciences Faculty Research and Publications. 910.
https://epublications.marquette.edu/bio_fac/910