TY - JOUR
T1 - Modeling Polyglutamine Pathogenesis in C. elegans
AU - Brignull, Heather R.
AU - Morley, James F.
AU - Garcia, Susana M.
AU - Morimoto, Richard I.
N1 - Funding Information:
We thank members of the Morimoto laboratory past and present, who contributed to this work both intellectually and technically. H. R. B. was supported by the Cellular and Molecular Biology of Disease Training Grant T32 GM08061 from the National Institute of General Medical Sciences (NIGMS) to Northwestern University. J. F. M. was supported by a Medical Scientist Training Grant from NIGMS to Northwestern University and an individual NRSA from the National Institute of Neurological Disease and Stroke. S. M. G. was supported by a PhD fellowship Praxis XXI BD/21451/99 from Fundação para a Ciência e Tecnologia. These studies were also supported by grants from NIGMS (GM38109), the National Institutes of Aging, the Huntington Disease Society of America Coalition for the Cure, and the Daniel F. and Ada L. Rice Foundation.
PY - 2006
Y1 - 2006
N2 - A growing number of human neurodegenerative diseases are associated with disruption of cellular protein folding homeostasis, leading to the appearance of misfolded proteins and deposition of protein aggregates and inclusions. Recent years have been witness to widespread development of invertebrate systems (specifically Drosophila and Caenorhabditis elegans) to model these disorders, bringing the many advantages of such systems, particularly the power of genetic analysis in a metazoan, to bear on these problems. In this chapter, we describe our studies using the nematode, C. elegans, as a model to study polyglutamine expansions as occur in Huntington's disease and related ataxias. Using fluorescently tagged polyglutamine repeats of different lengths, we have examined the dynamics of aggregate formation both within individual cells and over time throughout the lifetime of individual organisms, identifying aging as an important physiological determinant of aggregation and toxicity. Expanding on these observations, we demonstrate that a genetic pathway regulating longevity can alter the time course of aging-related polyglutamine-mediated phenotypes. To identify novel targets and better understand how cells sense and respond to the appearance of misfolded and aggregation-prone proteins, we use a genome-wide RNA interference-based genetic screen to identify modifiers of age-dependent polyglutamine aggregation. Throughout these studies, we used fluorescence-based, live-cell biological and biophysical methods to study the behavior of these proteins in a complex multicellular environment.
AB - A growing number of human neurodegenerative diseases are associated with disruption of cellular protein folding homeostasis, leading to the appearance of misfolded proteins and deposition of protein aggregates and inclusions. Recent years have been witness to widespread development of invertebrate systems (specifically Drosophila and Caenorhabditis elegans) to model these disorders, bringing the many advantages of such systems, particularly the power of genetic analysis in a metazoan, to bear on these problems. In this chapter, we describe our studies using the nematode, C. elegans, as a model to study polyglutamine expansions as occur in Huntington's disease and related ataxias. Using fluorescently tagged polyglutamine repeats of different lengths, we have examined the dynamics of aggregate formation both within individual cells and over time throughout the lifetime of individual organisms, identifying aging as an important physiological determinant of aggregation and toxicity. Expanding on these observations, we demonstrate that a genetic pathway regulating longevity can alter the time course of aging-related polyglutamine-mediated phenotypes. To identify novel targets and better understand how cells sense and respond to the appearance of misfolded and aggregation-prone proteins, we use a genome-wide RNA interference-based genetic screen to identify modifiers of age-dependent polyglutamine aggregation. Throughout these studies, we used fluorescence-based, live-cell biological and biophysical methods to study the behavior of these proteins in a complex multicellular environment.
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U2 - 10.1016/S0076-6879(06)12016-9
DO - 10.1016/S0076-6879(06)12016-9
M3 - Review article
C2 - 17046663
AN - SCOPUS:33749633639
SN - 0076-6879
VL - 412
SP - 256
EP - 282
JO - Methods in Enzymology
JF - Methods in Enzymology
ER -