Calpain-cleavage of Alpha-Synuclein: Connecting Proteolytic Processing to Disease-Linked Aggregation

Am J Pathol. 2007 May;170(5):1725-38. doi: 10.2353/ajpath.2007.061232.

Abstract

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are both characterized pathologically by the presence of neuronal inclusions termed Lewy bodies (LBs). A common feature found in LBs are aggregates of alpha-synuclein (alpha-Syn), and although it is now recognized that alpha-Syn is the major building block for these toxic filaments, the mechanism of how this occurs remains unknown. In the present study, we demonstrate that proteolytic processing of alpha-Syn by the protease calpain I leads to the formation of aggregated high-molecular weight species and adoption of a beta-sheet structure. To determine whether calpain-cleavage of alpha-Syn occurs in PD and DLB, we designed site-directed calpain-cleavage antibodies to alpha-Syn and tested their utility in several animal model systems. Detection of calpain-cleaved alpha-Syn was evident in mouse models of cerebral ischemia and PD and in a Drosophila model of PD. In the human PD and DLB brain, calpain-cleaved alpha-Syn antibodies immunolabeled LBs and neurites in the substantia nigra. Moreover, calpain-cleaved alpha-Syn fragments identified within LBs colocalized with activated calpain in neurons of the PD and DLB brains. These findings suggest that calpain I may participate in the disease-linked aggregation of alpha-Syn in various alpha-synucleinopathies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Animals
  • Area Under Curve
  • Blotting, Western
  • Brain / metabolism*
  • Calpain / metabolism*
  • Cell Line, Tumor
  • Drosophila
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Lewy Body Disease / metabolism*
  • Lewy Body Disease / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Neurons / metabolism
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Protein Structure, Secondary
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / metabolism*

Substances

  • alpha-Synuclein
  • Calpain