ER stress and unfolded protein response in amyotrophic lateral sclerosis

Kohsuke Kanekura, Hiroaki Suzuki, Sadakazu Aiso, Masaaki Matsuoka

Research output: Contribution to journalReview articlepeer-review

128 Citations (Scopus)


Several theories on the pathomechanism of amyotrophic lateral sclerosis (ALS) have been proposed: misfolded protein aggregates, mitochondrial dysfunction, increased glutamate toxicity, increased oxidative stress, disturbance of intracellular trafficking, and so on. In parallel, a number of drugs that have been developed to alleviate the putative key pathomechanism of ALS have been under clinical trials. Unfortunately, however, almost all studies have finished unsuccessfully. This fact indicates that the key ALS pathomechanism still remains a tough enigma. Recent studies with autopsied ALS patients and studies using mutant SOD1 (mSOD1) transgenic mice have suggested that endoplasmic reticulum (ER) stress-related toxicity may be a relevant ALS pathomechanism. Levels of ER stress-related proteins were upregulated in motor neurons in the spinal cords of ALS patients. It was also shown that mSOD1, translocated to the ER, caused ER stress in neurons in the spinal cord of mSOD1 transgenic mice. We recently reported that the newly identified ALS-causative gene, vesicle-associated membrane protein-associated protein B (VAPB), plays a pivotal role in unfolded protein response (UPR), a physiological reaction against ER stress. The ALS-linked P56S mutation in VAPB nullifies the function of VAPB, resulting in motoneuronal vulnerability to ER stress. In this review, we summarize recent advances in research on the ALS pathomechanism especially addressing the putative involvement of ER stress and UPR dysfunction.

Original languageEnglish
Pages (from-to)81-89
Number of pages9
JournalMolecular Neurobiology
Issue number2
Publication statusPublished - 2009 Apr


  • Amyotrophic lateral sclerosis
  • ER stress
  • Unfolded protein response

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


Dive into the research topics of 'ER stress and unfolded protein response in amyotrophic lateral sclerosis'. Together they form a unique fingerprint.

Cite this