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.
Koyama
Shingo
S
Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
Arawaka
Shigeki
S
Chang-Hong
Ren
R
Wada
Manabu
M
Kawanami
Toru
T
Kurita
Keiji
K
Kato
Masaaki
M
Nagai
Makiko
M
Aoki
Masashi
M
Itoyama
Yasuto
Y
Sobue
Gen
G
Chan
Pak H
PH
Kato
Takeo
T
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