An in vitro model for Lewy body-like hyaline inclusion/astrocytic hyaline inclusion: induction by ER stress with an ALS-linked SOD1 mutation.
Neuronal Lewy body-like hyaline inclusions (LBHI) and astrocytic hyaline inclusions (Ast-HI) containing mutant Cu/Zn superoxide dismutase 1 (SOD1) are morphological hallmarks of familial amyotrophic lateral sclerosis (FALS) associated with mutant SOD1. However, the mechanisms by which mutant SOD1 contributes to formation of LBHI/Ast-HI in FALS remain poorly defined. Here, we report induction of LBHI/Ast-HI-like hyaline inclusions (LHIs) in vitro by ER stress in neuroblastoma cells. These LHI closely resemble LBHI/Ast-HI in patients with SOD1-linked FALS. LHI and LBHI/Ast-HI share the following features: 1) eosinophilic staining with a pale core, 2) SOD1, ubiquitin and ER resident protein (KDEL) positivity and 3) the presence of approximately 15-25 nm granule-coated fibrils, which are morphological hallmark of mutant SOD1-linked FALS. Moreover, in spinal cord neurons of L84V SOD1 transgenic mice at presymptomatic stage, we observed aberrant aggregation of ER and numerous free ribosomes associated with abnormal inclusion-like structures, presumably early stage neuronal LBHI. We conclude that the LBHI/Ast-HI seen in human patients with mutant SOD1-linked FALS may arise from ER dysfunction.
Yamagishi
Satoru
S
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. yamagishi@neuro.mpg.de
Koyama
Yoshihisa
Y
Katayama
Taiichi
T
Taniguchi
Manabu
M
Hitomi
Junichi
J
Kato
Masaaki
M
Aoki
Masashi
M
Itoyama
Yasuto
Y
Kato
Shinsuke
S
Tohyama
Masaya
M
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016631:Lewy Bodies / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D012270:Ribosomes / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D025801:Ubiquitin / Q000737:chemistry
C000606290:SOD1 protein, human; D025801:Ubiquitin; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1