MICROSCOPY Vol.44▶No.3 2009
â– Researches Today

Amyotrophic Lateral Screlosis (ALS) and Endoplasmic Reticulum Stress

Taiichi Katayama

Abstract: Neuronal Lewy body-like hyaline inclusions (LBHI) and astrocytic hyaline inclusions (Ast-HI) containing mutant superoxide dismutase 1 (SOD1) are morphological hallmarks of familial amyotrophic lateral sclerosis (FALS) associated with mutant SOD1. However, little is known that the mechanisms by which mutant SOD1 contributes to formation of LBHI/Ast-HI in FALS. Here, we show induction of LBHI/Ast-HI-like hyaline inclusions (LHIs) in vitro by ER stress in SK-N-SH 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.

Key words: amyotrophic lateral screlosis, SOD1, endoplasmic reticulum, Lewy body-like hyaline inclusions