TY - JOUR
T1 - Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity
AU - Weisberg, Sarah J.
AU - Lyakhovetsky, Roman
AU - Werdiger, Ayelet-chen
AU - Gitler, Aaron D.
AU - Soen, Yoav
AU - Kaganovich, Daniel
N1 - Israel Science Foundation [843/11]; National Institute for Psychobiology in IsraelWe thank R. Morimoto, M. Brandeis, N. Dantuma, B. Florea, A. Kakizuka, H. Kampinga, A. Kisselev, S. Munro, H. Overkleeft, and M. Sherman for generous gifts of reagents; and M. Hecht, J. Goodhouse, and R. Sharivkin for technical assistance and advice. We also thank Jeremy England, Ehud Cohen, Michael Hecht, Mark Kaganovich, Maya Schuldiner, Hali Spokoini, and members of the D. K. laboratory for valuable discussion of the experiments and comments on the manuscript. This work was supported by Israel Science Foundation Grant 843/11 and a grant from the National Institute for Psychobiology in Israel.
PY - 2012/9/25
Y1 - 2012/9/25
N2 - Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role inmodulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability.
AB - Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role inmodulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability.
UR - http://www.scopus.com/inward/record.url?scp=84866883258&partnerID=8YFLogxK
U2 - 10.1073/pnas.1205829109
DO - 10.1073/pnas.1205829109
M3 - مقالة
SN - 0027-8424
VL - 109
SP - 15811
EP - 15816
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 39
ER -