ALS-linked mutant SOD1 proteins promote Aβ aggregates in ALS through direct interaction with Aβ

Ja Young Jang, Hyungmin Cho, Hye Yoon Park, Hyangshuk Rhim, Seongman Kang

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons. Aggregation of ALS-linked mutant Cu/Zn superoxide dismutase (SOD1) is a hallmark of a subset of familial ALS (fALS). Recently, intracellular amyloid-β (Aβ) is detected in motor neurons of both sporadic and familial ALS. We have previously shown that intracellular Aβ specifically interacts with G93A, an ALS-linked SOD1 mutant. However, little is known about the pathological and biological effect of this interaction in neurons. In this study, we have demonstrated that the Aβ-binding region is exposed on the SOD1 surface through the conformational changes due to misfolding of SOD1. Interestingly, we found that the intracellular aggregation of Aβ is enhanced through the direct interaction of Aβ with the Aβ-binding region exposed to misfolded SOD1. Ultimately, increased Aβ aggregation by this interaction promotes neuronal cell death. Consistent with this result, Aβ aggregates was three-fold higher in the brains of G93A transgenic mice than those of non Tg. Our study provides the first direct evidence that Aβ, an AD-linked factor, is associated to the pathogenesis of ALS and provides molecular clues to understand common aggregation mechanisms in the pathogenesis of neurodegenerative diseases. Furthermore, it will provide new insights into the development of therapeutic approaches for ALS.

Original languageEnglish
Pages (from-to)697-707
Number of pages11
JournalBiochemical and biophysical research communications
Issue number1
Publication statusPublished - 2017 Nov 4

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.


  • ALS
  • Amyloid beta (Aß)
  • Misfolded protein
  • Neurodegenerative disease
  • SOD1

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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