Formation of advanced glycation end-product-modified superoxide dismutase-1 (SOD1) is one of the mechanisms responsible for inclusions common to familial amyotrophic lateral sclerosis patients with SOD1 gene mutation, and transgenic mice expressing human SOD1 gene mutation

Shinsuke Kato, Kenji Nakashima, Seikoh Horiuchi, Ryoji Nagai, Don W. Cleveland, Jian Liu, Asao Hirano, Miki Takikawa, Masako Kato, Imaharu Nakano, Saburo Sakoda, Kohtaro Asayama, Eisaku Ohama

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Neuronal Lewy body-like hyaline inclusions (LBHI) and astrocytic hyaline inclusions (Ast-HI) are morphological hallmarks of certain familial amyotrophic lateral sclerosis (FALS) patients with superoxide dismutase-1 (SOD1) gene mutations, and transgenic mice expressing the human SOD1 gene mutation. The ultrastructure of inclusions in both diseases is identical: the essential common constituents are granule-coated fibrils approximately 15-25nm in diameter and granular materials. Detailed immunohistochemical analyses have shown that the essential common protein of the inclusions in both diseases is an SOD1 protein. This finding, together with the immunoelectron microscopy finding that the abnormal granule-coated fibrils comprising the inclusions are positive for SOD1, indicates that these granule-coated fibrils containing SOD1 are important evidence for mutant SOD1-linked disease in human and mouse. For immunoelectron microscopy, the granule-coated fibrils are modified by advanced glycation endproducts (AGE) such as Nε-carboxymethyl lysine, pyrraline and pentosidine (Maillard reaction). Based on the fact that AGE themselves are insoluble molecules with direct cytotoxic effects, the granule-coated fibrils and granular materials are not digested by the lysosomal and ubiquitin systems. The neurons and astrocytes of the normal individuals and non-transgenic mice show no significant immunoreactivity for AGE. Considered with the mutant-SOD1 aggregation toxicity, a portion of the SOD1 comprising both types of the inclusion is modified by the AGE, and the formation of the AGE-modified SOD1 (probably AGE-modified mutant SOD1) is one of the mechanisms responsible for the aggregation (i.e. granule-coated fibril formation).

Original languageEnglish (US)
Pages (from-to)67-81
Number of pages15
JournalNeuropathology
Volume21
Issue number1
DOIs
StatePublished - 2001

Keywords

  • Advanced glycation endproducts (AGE)
  • Astrocytic hyaline inclusions (Ast-HI)
  • Familial amyotrophic lateral sclerosis (FALS)
  • Granule-coated fibrils
  • Maillard reaction
  • Neuronal Lewy body-like hyaline inclusions (LBHI)
  • Superoxide dismutase-1 (SOD1)

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology

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