LRRK2 interactions with α-synuclein in Parkinson's disease brains and in cell models

J Mol Med (Berl). 2013 Apr;91(4):513-22. doi: 10.1007/s00109-012-0984-y. Epub 2012 Nov 27.

Abstract

Mutations in the genes encoding leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are associated with both autosomal dominant and idiopathic forms of Parkinson's disease (PD). α-Synuclein is the main protein in Lewy bodies, hallmark inclusions present in both sporadic and familial PD. We show that in PD brain tissue, the levels of LRRK2 are positively related to the increase in α-synuclein phosphorylation and aggregation in affected brain regions (amygdala and anterior cingulate cortex), but not in the unaffected visual cortex. In disease-affected regions, we show co-localization of these two proteins in neurons and Lewy body inclusions. Further, in vitro experiments show a molecular interaction between α-synuclein and LRRK2 under endogenous and over-expression conditions. In a cell culture model of α-synuclein inclusion formation, LRRK2 co-localizes with the α-synuclein inclusions, and knocking down LRRK2 increases the number of smaller inclusions. In addition to providing strong evidence for an interaction between LRRK2 and α-synuclein, our results shed light on the complex relationship between these two proteins in the brains of patients with PD and the underlying molecular mechanisms of the disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Cell Line
  • Disease Models, Animal
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mice
  • Mice, Knockout
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • alpha-Synuclein / metabolism*

Substances

  • alpha-Synuclein
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases