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Isoaspartate formation and neurodegeneration in Alzheimer's disease.

Abstract
We reviewed here that protein isomerization is enhanced in amyloid-beta peptides (Abeta) and paired helical filaments (PHFs) purified from Alzheimer's disease (AD) brains. Biochemical analyses revealed that Abeta purified from senile plaques and vascular amyloid are isomerized at Asp-1 and Asp-7. A specific antibody recognizing isoAsp-23 of Abeta further suggested the isomerization of Abeta at Asp-23 in vascular amyloid as well as in the core of senile plaques. Biochemical analyses of purified PHFs also revealed that heterogeneous molecular weight tau contains L-isoaspartate at Asp-193, Asn-381, and Asp-387, indicating a modification, other than phosphorylation, that differentiates between normal tau and PHF tau. Since protein isomerization as L-isoaspartate causes structural changes and functional inactivation, or enhances the aggregation process, this modification is proposed as one of the progression factors in AD. Protein L-isoaspartyl methyltransferase (PIMT) is suggested to play a role in the repair of isomerized proteins containing L-isoaspartate. We show here that PIMT is upregulated in neurodegenerative neurons and colocalizes in neurofibrillary tangles (NFTs) in AD. Taken together with the enhanced protein isomerization in AD brains, it is implicated that the upregulated PIMT may associate with increased protein isomerization in AD. We also reviewed studies on PIMT-deficient mice that confirmed that PIMT plays a physiological role in the repair of isomerized proteins containing L-isoaspartate. The knockout study also suggested that the brain of PIMT-deficient mice manifested neurodegenerative changes concomitant with accumulation of L-isoaspartate. We discuss the pathological implications of protein isomerization in the neurodegeneration found in model mice and AD.
AuthorsT Shimizu, A Watanabe, M Ogawara, H Mori, T Shirasawa
JournalArchives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 381 Issue 2 Pg. 225-34 (Sep 15 2000) ISSN: 0003-9861 [Print] United States
PMID11032409 (Publication Type: Journal Article, Review)
Chemical References
  • Amyloid beta-Peptides
  • tau Proteins
  • Aspartic Acid
  • Protein Methyltransferases
  • Protein D-Aspartate-L-Isoaspartate Methyltransferase
Topics
  • Alzheimer Disease (etiology, metabolism, pathology)
  • Amino Acid Sequence
  • Amyloid beta-Peptides (chemistry, genetics, metabolism)
  • Animals
  • Aspartic Acid (biosynthesis)
  • Blood Vessels (metabolism)
  • Brain (metabolism, pathology)
  • Cerebrovascular Circulation
  • Humans
  • In Vitro Techniques
  • Isomerism
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Nerve Degeneration (metabolism)
  • Plaque, Amyloid (metabolism, pathology)
  • Protein D-Aspartate-L-Isoaspartate Methyltransferase
  • Protein Methyltransferases (deficiency, genetics, metabolism)
  • Protein Processing, Post-Translational
  • tau Proteins (chemistry, genetics, metabolism)

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