Alteration of familial ALS-linked mutant SOD1 solubility with disease progression: its modulation by the proteasome and Hsp70.
Accumulation of misfolded Cu/Zn superoxide dismutase (SOD1) occurs in patients with a subgroup of familial amyotrophic lateral sclerosis (fALS). To identify the conversion of SOD1 from a normally soluble form to insoluble aggregates, we investigated the change of SOD1 solubility with aging in fALS-linked H46R SOD1 transgenic mice. Mutant SOD1 specifically altered to insoluble forms, which were sequentially separated into Triton X-100-insoluble/sodium dodecyl sulfate (SDS)-soluble and SDS-insoluble/formic acid-soluble species. In spinal cords, the levels of SDS-dissociable soluble SOD1 monomers and SDS-stable soluble dimers were significantly elevated before motor dysfunction onset. In COS-7 cells expressing H46R SOD1, treatment with proteasome inhibitors recapitulated the alteration of SOD1 solubility in transgenic mice. In contrast, overexpression of Hsp70 reduced accumulation of mutant-specific insoluble SOD1. SDS-soluble low molecular weight species of H46R SOD1 may appear as early misfolded intermediates when their concentration exceeds the capacity of the proteasome and molecular chaperones.
Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
Shingo
S
Koyama
Shigeki
S
Arawaka
Ren
R
Chang-Hong
Manabu
M
Wada
Toru
T
Kawanami
Keiji
K
Kurita
Masaaki
M
Kato
Makiko
M
Nagai
Masashi
M
Aoki
Yasuto
Y
Itoyama
Gen
G
Sobue
Pak H
PH
Chan
Takeo
T
Kato
D000367:Age Factors; D000375:Aging; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018450:Disease Progression; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D017510:Protein Folding; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D012995:Solubility; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics*; D000072105:Superoxide Dismutase-1
D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D061988:Proteasome Inhibitors; C000606290:SOD1 protein, human; D012967:Sodium Dodecyl Sulfate; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D046988:Proteasome Endopeptidase Complex