TY - JOUR
T1 - Characterization and Hsp104-induced artificial clearance of familial ALS-related SOD1 aggregates
AU - Kim, Yongmin
AU - Park, Ju Hwang
AU - Jang, Ja Young
AU - Rhim, Hyangshuk
AU - Kang, Seongman
N1 - Funding Information:
This work was supported by the Korea Healthcare Technology R&D Project , Ministry for Health, Welfare & Family Affairs , the Republic of Korea ( A101254 ), and by NRF grant funded by the Korea government (MEST) (No. R1203241).
PY - 2013/5/10
Y1 - 2013/5/10
N2 - Hsp104, a molecular chaperone protein, originates from Saccharomyces cerevisiae and shows potential for development as a therapeutic disaggregase for the treatment of neurodegenerative disorders. This study shows that aggregates of mutant superoxide dismutase 1 (SOD1), which cause amyotrophic lateral sclerosis (ALS), are disaggregated by Hsp104 in an ATP-dependent manner. Mutant SOD1 aggregates were first characterized using fluorescence loss in photobleaching experiments based on the reduced mobility of aggregated proteins. Hsp104 restored the mobility of mutant SOD1 proteins to a level comparable with that of the wild-type. However, ATPase-deficient Hsp104 mutants did not restore mobility, suggesting that, rather than preventing aggregation, Hsp104 disaggregates mutant SOD1 after it has aggregated. Despite the restored mobility, however, mutant SOD1 proteins existed as trimers or other higher-order structures, rather than as naturally occurring dimers. This study sheds further light on the mechanisms underlying the disaggregation of SOD1 mutant aggregates in ALS.
AB - Hsp104, a molecular chaperone protein, originates from Saccharomyces cerevisiae and shows potential for development as a therapeutic disaggregase for the treatment of neurodegenerative disorders. This study shows that aggregates of mutant superoxide dismutase 1 (SOD1), which cause amyotrophic lateral sclerosis (ALS), are disaggregated by Hsp104 in an ATP-dependent manner. Mutant SOD1 aggregates were first characterized using fluorescence loss in photobleaching experiments based on the reduced mobility of aggregated proteins. Hsp104 restored the mobility of mutant SOD1 proteins to a level comparable with that of the wild-type. However, ATPase-deficient Hsp104 mutants did not restore mobility, suggesting that, rather than preventing aggregation, Hsp104 disaggregates mutant SOD1 after it has aggregated. Despite the restored mobility, however, mutant SOD1 proteins existed as trimers or other higher-order structures, rather than as naturally occurring dimers. This study sheds further light on the mechanisms underlying the disaggregation of SOD1 mutant aggregates in ALS.
KW - Amyotrophic lateral sclerosis
KW - FLIP
KW - Hsp104
KW - Mutant SOD1
KW - SOD1 aggregate
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U2 - 10.1016/j.bbrc.2013.03.107
DO - 10.1016/j.bbrc.2013.03.107
M3 - Article
C2 - 23583391
AN - SCOPUS:84880488965
SN - 0006-291X
VL - 434
SP - 521
EP - 526
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -